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Alva‐Ruiz R, Watkins RD, Tomlinson JL, Yonkus JA, Abdelrahman AM, Conboy CB, Jessen E, Werneburg NW, Kuipers H, Sample JW, Gores GJ, Ilyas SI, Truty MJ, Smoot RL. YAP-TEAD inhibition is associated with upregulation of an androgen receptor mediated transcription program providing therapeutic escape. FEBS Open Bio 2024; 14:1873-1887. [PMID: 39300603 PMCID: PMC11532981 DOI: 10.1002/2211-5463.13901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 08/08/2024] [Accepted: 09/11/2024] [Indexed: 09/22/2024] Open
Abstract
Cholangiocarcinoma (CCA) is a highly aggressive form of liver cancer and is an increasing cause of cancer-related death worldwide. Despite its increasing incidence globally and alarming mortality, treatment options for CCA have largely remained unchanged, stressing the importance of developing new effective therapies. YAP activation is common in CCA, and its major transcriptional signaling partners are the TEAD proteins. CA3 is a small-molecule YAP-TEAD disrupter discovered utilizing a TEAD reporter assay. Utilizing CCA, gastric cancer cell lines, and patient-derived xenograft models (PDX), we demonstrate that CA3 is effective in inducing cell death and delaying tumor growth in both FGFR2 fusion and wild-type models. CA3 was associated with on-target decreases in YAP-TEAD target gene expression, TEAD reporter activity, and overall TEAD levels. Hippo pathway signaling was not altered as there was no change in YAP phosphorylation status in the cells exposed to CA3. RNA sequencing of gastric cancer and CCA models demonstrated upregulation of an androgen receptor-mediated transcriptional program following exposure to CA3 in five unique models tested. Consistent with this upstream regulator analysis, CA3 exposure in CCA cells was associated with increased AR protein levels, and combinatorial therapy with CA3 and androgen receptor blockade was associated with increased cancer cell death. CA3 behaves functionally as a YAP-TEAD disrupter in the models tested and demonstrated therapeutic efficacy. Exposure to CA3 was associated with compensatory androgen receptor signaling and dual inhibition improved the therapeutic effect.
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Affiliation(s)
- Roberto Alva‐Ruiz
- Division of Hepatobiliary & Pancreas Surgery, Department of SurgeryMayo ClinicRochesterMNUSA
| | - Ryan D. Watkins
- Division of Hepatobiliary & Pancreas Surgery, Department of SurgeryMayo ClinicRochesterMNUSA
| | - Jennifer L. Tomlinson
- Division of Hepatobiliary & Pancreas Surgery, Department of SurgeryMayo ClinicRochesterMNUSA
| | - Jennifer A. Yonkus
- Division of Hepatobiliary & Pancreas Surgery, Department of SurgeryMayo ClinicRochesterMNUSA
| | - Amro M. Abdelrahman
- Division of Hepatobiliary & Pancreas Surgery, Department of SurgeryMayo ClinicRochesterMNUSA
| | - Caitlin B. Conboy
- Division of Medical Oncology, Department of OncologyMayo ClinicRochesterMNUSA
| | - Erik Jessen
- Division of Biomedical Statistics and Informatics, Department of Research ServicesMayo ClinicRochesterMNUSA
| | - Nathan W. Werneburg
- Division of Gastroenterology & Hepatology, Department of MedicineMayo ClinicRochesterMNUSA
| | - Hendrien Kuipers
- Division of Hepatobiliary & Pancreas Surgery, Department of SurgeryMayo ClinicRochesterMNUSA
| | - Jack W. Sample
- Division of Hepatobiliary & Pancreas Surgery, Department of SurgeryMayo ClinicRochesterMNUSA
| | - Gregory J. Gores
- Division of Gastroenterology & Hepatology, Department of MedicineMayo ClinicRochesterMNUSA
| | - Sumera I. Ilyas
- Division of Gastroenterology & Hepatology, Department of MedicineMayo ClinicRochesterMNUSA
- Department of ImmunologyMayo ClinicRochesterMNUSA
| | - Mark J. Truty
- Division of Hepatobiliary & Pancreas Surgery, Department of SurgeryMayo ClinicRochesterMNUSA
| | - Rory L. Smoot
- Division of Hepatobiliary & Pancreas Surgery, Department of SurgeryMayo ClinicRochesterMNUSA
- Department of Biochemistry and Molecular BiologyMayo ClinicRochesterMNUSA
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Uson Junior PLS, Araujo RLC. Immunotherapy in biliary tract cancers: Current evidence and future perspectives. World J Gastrointest Oncol 2022; 14:1446-1455. [PMID: 36160750 PMCID: PMC9412936 DOI: 10.4251/wjgo.v14.i8.1446] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 04/30/2022] [Accepted: 07/06/2022] [Indexed: 02/05/2023] Open
Abstract
Bile duct tumors are comprised of tumors that originate from both intrahepatic and extrahepatic bile ducts and gallbladder tumors. These are aggressive tumors and chemotherapy is still the main treatment for advanced-stage disease and most of these cases have a poor overall survival. Strategies are aimed at treatments with better outcomes and less toxicity which makes immunotherapy an area of significant importance. Recent Food and Drug Administration approvals of immune checkpoint inhibitors (ICI) for agnostic tumors based on biomarkers such as microsatellite instability-high and tumor mutation burden-high are important steps in the treatment of patients with advanced bile duct tumors. Despite limited responses with isolated checkpoint inhibitors in later lines of systemic treatment in advanced disease, drug combination strategies have been demonstrating encouraging results to enhance ICI efficacy.
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Affiliation(s)
| | - Raphael LC Araujo
- Department of Surgery, Universidade Federal de São Paulo, São Paulo 04039-002, Brazil
- Department of Oncology, Hospital Israelita Albert Einstein, São Paulo 05652-900, Brazil
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3
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Casak SJ, Pradhan S, Fashoyin-Aje LA, Ren Y, Shen YL, Xu Y, Chow ECY, Xiong Y, Zirklelbach JF, Liu J, Charlab R, Pierce WF, Fesenko N, Beaver JA, Pazdur R, Kluetz PG, Lemery SJ. FDA Approval Summary: Ivosidenib for the Treatment of Patients with Advanced Unresectable or Metastatic, Chemotherapy Refractory Cholangiocarcinoma with an IDH1 Mutation. Clin Cancer Res 2022; 28:2733-2737. [PMID: 35259259 PMCID: PMC9250596 DOI: 10.1158/1078-0432.ccr-21-4462] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/27/2022] [Accepted: 02/21/2022] [Indexed: 01/03/2023]
Abstract
On August 25, 2021, the FDA approved ivosidenib for the treatment of adult patients with unresectable locally advanced or metastatic hepatocellular isocitrate dehydrogenase 1 (IDH1) mutated cholangiocarcinoma (CCA) as detected by an FDA-approved test with disease progression after 1 to 2 prior lines of systemic therapy for advanced disease. The approval was based on data from Study AG120-C-005 (ClarIDHy), a double-blind placebo-controlled trial that randomly allocated (2:1) patients to receive either ivosidenib or placebo. Independently assessed progression-free survival (PFS) was the primary endpoint. With a median follow-up of 6.9 months, the HR for PFS was 0.37 [95% confidence interval (CI), 0.25-0.54; P < 0.0001). Overall survival (OS) was the key secondary endpoint. At the final analysis of OS, with 70.5% of patients in the placebo arm receiving ivosidenib post disease progression, a non-statistically significant improvement in the ivosidenib arm with an HR = 0.79 (95% CI, 0.56-1.12) and median OS of 10.3 months (95% CI, 7.8-12.4) and 7.5 months (95% CI, 4.8-11.1) in the ivosidenib and placebo arms, respectively, were reported. Adverse reactions occurring in >20% of patients receiving ivosidenib were fatigue/asthenia, nausea, diarrhea, abdominal pain, ascites, vomiting, cough, and decreased appetite. Adverse reactions occurring in >20% of patients receiving placebo were fatigue/asthenia, nausea, abdominal pain, and vomiting. This is the first approval for the subset of patients with CCA harboring an IDH1 mutation.
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Affiliation(s)
- Sandra J. Casak
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Shan Pradhan
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | | | - Yi Ren
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Yuan-Li Shen
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Yuan Xu
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | | | - Ye Xiong
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | | | - Jiang Liu
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Rosane Charlab
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - William F. Pierce
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Nataliya Fesenko
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
| | - Julia A. Beaver
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration;,Oncology Center of Excellence, U.S. Food and Drug Administration
| | - Richard Pazdur
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration;,Oncology Center of Excellence, U.S. Food and Drug Administration
| | - Paul G. Kluetz
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration;,Oncology Center of Excellence, U.S. Food and Drug Administration
| | - Steven J. Lemery
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration
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4
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Twohig P, Peeraphatdit TB, Mukherjee S. Current status of liver transplantation for cholangiocarcinoma. World J Gastrointest Surg 2022; 14:1-11. [PMID: 35126858 PMCID: PMC8790328 DOI: 10.4240/wjgs.v14.i1.1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/12/2022] [Accepted: 12/28/2021] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the second most common liver cancer with a median survival of 12-24 mo without treatment. It is further classified based on its location into intrahepatic CCA (iCCA), perihilar CCA (pCCA), and distal CCA. Surgical resection is the mainstay of treatment, but up to 70% of these tumors are inoperable at the time of diagnosis. CCA was previously an absolute contraindication for liver transplantation (LT) due to poor outcomes primary due to early recurrent disease. However, improvement in patient selection criteria and neoadjuvant treatment protocols have improved outcomes for inoperable pCCA patients with recent studies reporting LT may improve survival in iCCA. Future advances in the treatment of CCA should include refining patient selection criteria and organ allocation for all subtypes of CCA, determining effective immunotherapies and the evolving role of personalized medicine in patients ineligible for surgical resection or LT. Our article reviews the current status of LT in CCA, along with future directions in managing patients with CCA.
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Affiliation(s)
- Patrick Twohig
- Department of Internal Medicine, Division of Gastroenterology and Transplant Hepatology, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Thoetchai Bee Peeraphatdit
- Department of Internal Medicine, Division of Gastroenterology and Transplant Hepatology, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Sandeep Mukherjee
- Department of Internal Medicine, Division of Gastroenterology, Creighton University, Omaha, NE 68124, United States
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5
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Prete MG, Cammarota A, D’Alessio A, Zanuso V, Rimassa L. Current options and future directions of systemic therapy for advanced biliary tract cancer. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2021; 2:416-433. [PMID: 36045701 PMCID: PMC9400707 DOI: 10.37349/etat.2021.00054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 09/09/2021] [Indexed: 11/19/2022] Open
Abstract
Biliary tract cancers (BTCs) are aggressive tumors arising from different portions of the biliary tree and classified according to the anatomical location in intrahepatic (i) cholangiocarcinoma (CCA, iCCA), perihilar CCA (pCCA), and distal CCA (dCCA), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC). Due to their silent behavior, BTCs are frequently diagnosed at advanced stages when the prognosis is poor. The available chemotherapeutic options are palliative and unfortunately, most patients will die from their disease between 6 and 18 months from diagnosis. However, over the last decade, amounting interest has been posed on the genomic landscape of BTCs and deep-sequencing studies have identified different potentially actionable driver mutations. Hence, the promising results of the early phase clinical studies with targeted agents against isocitrate dehydrogenase (IDH) 1 mutation or fibroblast growth factor (FGF) receptor (FGFR) 2 aberrations inintrahepatic tumors, and other agents against humanepidermal growth factor receptor (HER) 2 overexpression/mutations, neurotrophic tyrosine receptor kinase (NTRK) fusions or B-type Raf kinase (BRAF) mutations across different subtypes of BTCs, have paved the way for a "precision medicine" strategy for BTCs. Moreover, despite the modest results when used as monotherapy, beyond microsatellite instability-high (MSI-H) tumors, immune checkpoint inhibitors are being evaluated in combination with platinum-based chemotherapy, possibly further expanding the therapeutic landscape of advanced BTCs. This review aims to provide an overview of the approved systemic therapies, the promising results, and the ongoing studies to explore the current and future directions of advanced BTC systemic treatment.
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Affiliation(s)
- Maria Giuseppina Prete
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Antonella Cammarota
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Antonio D’Alessio
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Valentina Zanuso
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
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6
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Boerner T, Drill E, Pak LM, Nguyen B, Sigel CS, Doussot A, Shin P, Goldman DA, Gonen M, Allen PJ, Balachandran VP, Cercek A, Harding J, Solit DB, Schultz N, Kundra R, Walch H, D’Angelica MI, DeMatteo RP, Drebin J, Kemeny NE, Kingham TP, Simpson AL, Hechtman JF, Vakiani E, Lowery MA, Ijzermans J, Buettner S, Groot Koerkamp B, Doukas M, Chandwani R, Jarnagin WR. Genetic Determinants of Outcome in Intrahepatic Cholangiocarcinoma. Hepatology 2021; 74:1429-1444. [PMID: 33765338 PMCID: PMC8713028 DOI: 10.1002/hep.31829] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 03/04/2021] [Accepted: 03/05/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIM Genetic alterations in intrahepatic cholangiocarcinoma (iCCA) are increasingly well characterized, but their impact on outcome and prognosis remains unknown. APPROACH AND RESULTS This bi-institutional study of patients with confirmed iCCA (n = 412) used targeted next-generation sequencing of primary tumors to define associations among genetic alterations, clinicopathological variables, and outcome. The most common oncogenic alterations were isocitrate dehydrogenase 1 (IDH1; 20%), AT-rich interactive domain-containing protein 1A (20%), tumor protein P53 (TP53; 17%), cyclin-dependent kinase inhibitor 2A (CDKN2A; 15%), breast cancer 1-associated protein 1 (15%), FGFR2 (15%), polybromo 1 (12%), and KRAS (10%). IDH1/2 mutations (mut) were mutually exclusive with FGFR2 fusions, but neither was associated with outcome. For all patients, TP53 (P < 0.0001), KRAS (P = 0.0001), and CDKN2A (P < 0.0001) alterations predicted worse overall survival (OS). These high-risk alterations were enriched in advanced disease but adversely impacted survival across all stages, even when controlling for known correlates of outcome (multifocal disease, lymph node involvement, bile duct type, periductal infiltration). In resected patients (n = 209), TP53mut (HR, 1.82; 95% CI, 1.08-3.06; P = 0.03) and CDKN2A deletions (del; HR, 3.40; 95% CI, 1.95-5.94; P < 0.001) independently predicted shorter OS, as did high-risk clinical variables (multifocal liver disease [P < 0.001]; regional lymph node metastases [P < 0.001]), whereas KRASmut (HR, 1.69; 95% CI, 0.97-2.93; P = 0.06) trended toward statistical significance. The presence of both or neither high-risk clinical or genetic factors represented outcome extremes (median OS, 18.3 vs. 74.2 months; P < 0.001), with high-risk genetic alterations alone (median OS, 38.6 months; 95% CI, 28.8-73.5) or high-risk clinical variables alone (median OS, 37.0 months; 95% CI, 27.6-not available) associated with intermediate outcome. TP53mut, KRASmut, and CDKN2Adel similarly predicted worse outcome in patients with unresectable iCCA. CDKN2Adel tumors with high-risk clinical features were notable for limited survival and no benefit of resection over chemotherapy. CONCLUSIONS TP53, KRAS, and CDKN2A alterations were independent prognostic factors in iCCA when controlling for clinical and pathologic variables, disease stage, and treatment. Because genetic profiling can be integrated into pretreatment therapeutic decision-making, combining clinical variables with targeted tumor sequencing may identify patient subgroups with poor outcome irrespective of treatment strategy.
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Affiliation(s)
- Thomas Boerner
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Esther Drill
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Linda M. Pak
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Bastien Nguyen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY;,Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Carlie S. Sigel
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Alexandre Doussot
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Paul Shin
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Debra A. Goldman
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Mithat Gonen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | | | | | - Andrea Cercek
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - James Harding
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - David B. Solit
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY;,Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Nikolaus Schultz
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY;,Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ritika Kundra
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY;,Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Henry Walch
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY;,Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | | | | | - Jeffrey Drebin
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Nancy E. Kemeny
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - T. Peter Kingham
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Amber L. Simpson
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada
| | - Jaclyn F. Hechtman
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Efsevia Vakiani
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | | | - J.N.M. Ijzermans
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - S. Buettner
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - B. Groot Koerkamp
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - M. Doukas
- Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
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7
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Wang C, Huang M, Geng Q, Li W, Chang J, Tang W, Guo W. Apatinib for patients with metastatic biliary tract carcinoma refractory to standard chemotherapy: results from an investigator-initiated, open-label, single-arm, exploratory phase II study. Ther Adv Med Oncol 2021; 13:17588359211039047. [PMID: 34484431 PMCID: PMC8411636 DOI: 10.1177/17588359211039047] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 07/26/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND There is no standard therapy for metastatic biliary tract carcinoma (BTC) refractory to first-line chemotherapy. Apatinib, a VEGFR2 tyrosine kynase inhibitor, showed an activity against BTC xenografts in preclinical models. We conducted an exploratory study to evaluate the efficacy and safety of apatinib in patients with metastatic BTC. METHODS This is a single-arm phase II study [ClinicalTrials.gov identifier: NCT03427242]. Eligible patients were aged 18 years or older; histologically confirmed metastatic BTC; refractory or intolerance to at least one chemotherapeutic regimen; no prior use of anti-angiogenic targeted drugs; Eastern Cooperative Oncology Group performance status of 0-2. Patients received oral apatinib 500 mg each day continuously until unacceptable toxicity or tumor progression. The primary endpoint was progress free survival (PFS). The secondary endpoint was overall survival (OS), objective response rate (ORR) and treatment safety. RESULTS A total of 22 patients were recruited. All of them received apatinib medication. The median age was 63 (44-75) years old. Twenty patients received efficacy evaluation after treatment. The objective response rate (ORR) and disease control rate (DCR) were 15.0% and 60.0%, respectively. The median PFS was 2.73 months [95% confidence interval (CI): 1.74-3.72 months], with 6 months PFS rate of 27.3% (95% CI: 8.7-45.9%). The median OS was 4.81 months (95% CI: 3.16-10.9 months), with 12 months OS rate of 36.4% (95% CI: 16.2-56.6%). Nine out of 22 patients (40.9%) had grade 3/4 adverse events. The most common grade 3/4 adverse events were hand-foot skin syndrome [three (13.6%) patients] and hypertension [two (9.1%) patients]. No treatment-related death occurred. CONCLUSIONS For patients with metastatic BTC, apatinib showed an anti-tumor activity with acceptable safety, which deserves the further clinical trial.This trial was prospectively registered on ClinicalTrials.gov [NCT03427242]. Date of first patient enrollment: 26 January 2018. Date of registration (date of first posted): 9 February 2018.
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Affiliation(s)
- Chenchen Wang
- Department of Medical Oncology, Fudan
University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical
College, Fudan University, Shanghai, China
| | - Mingzhu Huang
- Department of Medical Oncology, Fudan
University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical
College, Fudan University, Shanghai, China
| | - Qirong Geng
- Department of Medical Oncology, Fudan
University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical
College, Fudan University, Shanghai, China
| | - Wenhua Li
- Department of Medical Oncology, Fudan
University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical
College, Fudan University, Shanghai, China
| | - Jinjia Chang
- Department of Medical Oncology, Fudan
University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical
College, Fudan University, Shanghai, China
| | - Wei Tang
- Department of Radiology, Fudan University
Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical
College, Fudan University, Shanghai, China
| | - Weijian Guo
- Department of Medical Oncology, Fudan
University Shanghai Cancer Center, Shanghai Medical College, Shanghai
200032, China
- Department of Radiology, Fudan University
Shanghai Cancer Center, Shanghai, China
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8
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Vallejo A, Erice O, Entrialgo-Cadierno R, Feliu I, Guruceaga E, Perugorria MJ, Olaizola P, Muggli A, Macaya I, O'Dell M, Ruiz-Fernandez de Cordoba B, Ortiz-Espinosa S, Hezel AF, Arozarena I, Lecanda F, Avila MA, Fernandez-Barrena MG, Evert M, Ponz-Sarvise M, Calvisi DF, Banales JM, Vicent S. FOSL1 promotes cholangiocarcinoma via transcriptional effectors that could be therapeutically targeted. J Hepatol 2021; 75:363-376. [PMID: 33887357 DOI: 10.1016/j.jhep.2021.03.028] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 03/10/2021] [Accepted: 03/25/2021] [Indexed: 01/27/2023]
Abstract
BACKGROUND & AIMS Cholangiocarcinoma (CCA) is a neoplasia of the biliary tract driven by genetic, epigenetic and transcriptional mechanisms. Herein, we investigated the role of the transcription factor FOSL1, as well as its downstream transcriptional effectors, in the development and progression of CCA. METHODS FOSL1 was investigated in human CCA clinical samples. Genetic inhibition of FOSL1 in human and mouse CCA cell lines was performed in in vitro and in vivo models using constitutive and inducible short-hairpin RNAs. Conditional FOSL1 ablation was done using a genetically engineered mouse (GEM) model of CCA (mutant KRAS and Trp53 knockout). Follow-up RNA and chromatin immunoprecipitation (ChIP) sequencing analyses were carried out and downstream targets were validated using genetic and pharmacological inhibition. RESULTS An inter-species analysis of FOSL1 in CCA was conducted. First, FOSL1 was found to be highly upregulated in human and mouse CCA, and associated with poor patient survival. Pharmacological inhibition of different signalling pathways in CCA cells converged on the regulation of FOSL1 expression. Functional experiments showed that FOSL1 is required for cell proliferation and cell cycle progression in vitro, and for tumour growth and tumour maintenance in both orthotopic and subcutaneous xenograft models. Likewise, FOSL1 genetic abrogation in a GEM model of CCA extended mouse survival by decreasing the oncogenic potential of transformed cholangiocytes. RNA and ChIP sequencing studies identified direct and indirect transcriptional effectors such as HMGCS1 and AURKA, whose genetic and pharmacological inhibition phenocopied FOSL1 loss. CONCLUSIONS Our data illustrate the functional and clinical relevance of FOSL1 in CCA and unveil potential targets amenable to pharmacological inhibition that could enable the implementation of novel therapeutic strategies. LAY SUMMARY Understanding the molecular mechanisms involved in cholangiocarcinoma (bile duct cancer) development and progression stands as a critical step for the development of novel therapies. Through an inter-species approach, this study provides evidence of the clinical and functional role of the transcription factor FOSL1 in cholangiocarcinoma. Moreover, we report that downstream effectors of FOSL1 are susceptible to pharmacological inhibition, thus providing new opportunities for therapeutic intervention.
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Affiliation(s)
- Adrián Vallejo
- University of Navarra, Centre for Applied Medical Research, Program in Solid Tumours, Pamplona, Spain
| | - Oihane Erice
- University of Navarra, Centre for Applied Medical Research, Program in Solid Tumours, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| | | | - Iker Feliu
- University of Navarra, Centre for Applied Medical Research, Program in Solid Tumours, Pamplona, Spain
| | - Elizabeth Guruceaga
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain; University of Navarra, Centre for Applied Medical Research, Computational Biology Program, Pamplona, Spain; ProteoRed-Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Maria J Perugorria
- University of the Basque Country, San Sebastian, Spain; Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital -, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain
| | - Paula Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital -, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Alexandra Muggli
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Irati Macaya
- University of Navarra, Centre for Applied Medical Research, Program in Solid Tumours, Pamplona, Spain
| | - Michael O'Dell
- University of Rochester Medical Centre, Rochester, NY, USA
| | | | - Sergio Ortiz-Espinosa
- University of Navarra, Centre for Applied Medical Research, Program in Solid Tumours, Pamplona, Spain
| | - Aram F Hezel
- University of Rochester Medical Centre, Rochester, NY, USA
| | - Imanol Arozarena
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain; Cancer Signalling Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), Pamplona, Spain
| | - Fernando Lecanda
- University of Navarra, Centre for Applied Medical Research, Program in Solid Tumours, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC, Instituto de Salud Carlos III), Madrid, Spain; University of Navarra, Department of Pathology, Anatomy and Physiology, Pamplona, Spain
| | - Matias A Avila
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain; University of Navarra, Centre for Applied Medical Research, Hepatology Program, Pamplona, Spain
| | - Maite G Fernandez-Barrena
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain; University of Navarra, Centre for Applied Medical Research, Hepatology Program, Pamplona, Spain
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | | | - Diego F Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital -, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain; Ikerbasque, Basque Foundation for Sciences, Bilbao, Spain
| | - Silve Vicent
- University of Navarra, Centre for Applied Medical Research, Program in Solid Tumours, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC, Instituto de Salud Carlos III), Madrid, Spain; University of Navarra, Department of Pathology, Anatomy and Physiology, Pamplona, Spain.
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9
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Gardrat S, Houy A, Brooks K, Cassoux N, Barnhill R, Dayot S, Bièche I, Raynal V, Baulande S, Marais R, Roman-Roman S, Stern MH, Rodrigues M. Definition of Biologically Distinct Groups of Conjunctival Melanomas According to Etiological Factors and Implications for Precision Medicine. Cancers (Basel) 2021; 13:3836. [PMID: 34359736 PMCID: PMC8345091 DOI: 10.3390/cancers13153836] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 07/19/2021] [Accepted: 07/26/2021] [Indexed: 02/06/2023] Open
Abstract
Conjunctival melanoma (ConjMel) is a potentially deadly ocular melanoma, originating from partially sunlight-exposed mucosa. We explored the mutational landscape of ConjMel and studied the correlation with etiological factors. We collected 47 primary ConjMel samples and performed next-generation sequencing of 400 genes. Hotspot mutations in BRAF, NRAS, HRAS, and KIT were observed in 16 (34%), 5 (11%), 2, and 2 cases, respectively. Patients with BRAF and CDKN2A-mutated ConjMel tended to be younger while the NF1-mutated one tended to be older. The eight tumors arising from nevi were enriched in CTNNB1 mutations (63% vs. 8%; Fisher's exact p-test = 0.001) compared to non-nevi ConjMel and five were devoid of BRAF, RAS, NF1, or KIT mutations, suggesting a specific oncogenic process in these tumors. The two KIT-mutated cases carried SF3B1 mutations and were located on sun-protected mucosa, a genotype shared with genital and anorectal mucosal melanomas. Targetable mutations were observed in ERBB2, IDH1, MET, and MAP2K1 (one occurrence each). Mutational landscape of ConjMel characterizes distinct molecular subtypes with oncogenic drivers common with mucosal and skin melanomas. CTNNB1 mutations were associated with nevus-derived ConjMel. Concomitant KIT/SF3B1 mutations in sun-protected cases suggest a common tumorigenic process with genital and anorectal mucosal melanomas.
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Affiliation(s)
- Sophie Gardrat
- INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe Labellisée par la Ligue Nationale Contre le Cancer and PSL Research University, Department of Biopathology, Institut Curie, PSL Research University, F-75005 Paris, France;
| | - Alexandre Houy
- INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe Labellisée par la Ligue Nationale Contre le Cancer, Department of Genetics, Institut Curie, PSL Research University, F-75005 Paris, France; (A.H.); (S.D.); (M.-H.S.)
| | - Kelly Brooks
- Molecular Oncology Group, CRUK Manchester Institute, The University of Manchester, Alderley Park, Manchester M13 9PL, UK; (K.B.); (R.M.)
- QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
| | - Nathalie Cassoux
- Department of Ocular Oncology, Faculty of Medicine, Institut Curie, Université de Paris Descartes, F-75005 Paris, France;
| | - Raymond Barnhill
- Department of Biopathology, Institut Curie, PSL Research University, F-75005 Paris, France;
| | - Stéphane Dayot
- INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe Labellisée par la Ligue Nationale Contre le Cancer, Department of Genetics, Institut Curie, PSL Research University, F-75005 Paris, France; (A.H.); (S.D.); (M.-H.S.)
| | - Ivan Bièche
- INSERM U1016, Institut Curie, Department of Genetics, Faculty of Pharmaceutical and Biological Sciences, Université de Paris, F-75005 Paris, France;
| | - Virginie Raynal
- Institut Curie Genomics of Excellence (ICGex) Platform, Institut Curie, PSL Research University, F-75005 Paris, France; (V.R.); (S.B.)
| | - Sylvain Baulande
- Institut Curie Genomics of Excellence (ICGex) Platform, Institut Curie, PSL Research University, F-75005 Paris, France; (V.R.); (S.B.)
| | - Richard Marais
- Molecular Oncology Group, CRUK Manchester Institute, The University of Manchester, Alderley Park, Manchester M13 9PL, UK; (K.B.); (R.M.)
| | - Sergio Roman-Roman
- Translational Research Department, Institut Curie, PSL Research University, F-75005 Paris, France;
| | - Marc-Henri Stern
- INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe Labellisée par la Ligue Nationale Contre le Cancer, Department of Genetics, Institut Curie, PSL Research University, F-75005 Paris, France; (A.H.); (S.D.); (M.-H.S.)
| | - Manuel Rodrigues
- INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe Labellisée par la Ligue Nationale Contre le Cancer, Department of Genetics, Institut Curie, PSL Research University, F-75005 Paris, France; (A.H.); (S.D.); (M.-H.S.)
- Department of Medical Oncology, Institut Curie, PSL Research University, F-75005, Paris, France
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10
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Massani M, Bonariol L, Stecca T. Hepatic Arterial Infusion Chemotherapy for Unresectable Intrahepatic Cholangiocarcinoma, a Comprehensive Review. J Clin Med 2021; 10:2552. [PMID: 34207700 PMCID: PMC8228250 DOI: 10.3390/jcm10122552] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/02/2021] [Accepted: 06/08/2021] [Indexed: 01/03/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the second most common primitive liver cancer. Despite recent advances in the surgical management, the prognosis remains poor, with a 5-year survival rate of less than 5%. Intrahepatic CCA (iCCA) has a median survival between 18 and 30 months, but if deemed unresectable it decreases to 6 months. Most patients have a liver-confined disease that is considered unresectable because of its localization, with infiltration of vascular structures or multifocality. The peculiar dual blood supply allows the delivery of high doses of chemotherapy via a surgically implanted subcutaneous pump, through the predominant arterial tumor vascularization, achieving much higher and more selective tumor drug levels than systemic administration. The results of the latest studies suggest that adequate and early treatment with the combination approach of hepatic arterial infusion (HAI) and systemic (SYS) chemotherapy is associated with improved progression-free and overall survival than SYS or HAI alone for the treatment of unresectable iCCA. Current recommendations are limited by a lack of prospective trials. Individualization of chemotherapy and regimens based on selective targets in mutant iCCA are a focus for future research. In this paper we present a comprehensive review of the studies published to date and ongoing trials.
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Affiliation(s)
- Marco Massani
- HPB Hub Reference Center, First General Surgery Unit, Department of Surgery, Azienda ULSS2 Marca Trevigiana, 31100 Treviso, Italy; (L.B.); (T.S.)
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11
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Cigliano A, Chen X, Calvisi DF. Current challenges to underpinning the genetic basis for cholangiocarcinoma. Expert Rev Gastroenterol Hepatol 2021; 15:511-526. [PMID: 33888034 PMCID: PMC8173760 DOI: 10.1080/17474124.2021.1915128] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 04/07/2021] [Indexed: 12/23/2022]
Abstract
AREAS COVERED This review provides an overview regarding the current scenario and knowledge of the CCA genomic landscape and the potentially actionable molecular aberrations in each CCA subtype. EXPERT OPINION The establishment and advances of high-throughput methodologies applied to genetic and epigenetic profiling are changing many cancer types' therapeutic landscape , including CCA.The large body of data generated must be interpreted appropriately and eventually implemented in clinical practice. The following advancements toward precision medicine in CCA management will require designing better clinical trials with improved methods to stratify biliary tumor patients.
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Affiliation(s)
- Antonio Cigliano
- Department of Medical, Surgery and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, Italy
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California, USA
| | - Diego F. Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
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12
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Molecularly targeted therapy for advanced gastrointestinal noncolorectal cancer treatment: how to choose? Past, present, future. Anticancer Drugs 2021; 32:593-601. [PMID: 33929995 DOI: 10.1097/cad.0000000000001071] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Gastrointestinal cancer is a leading cause of death worldwide. Conventional cytotoxic chemotherapy has been the backbone of advanced gastrointestinal cancer treatment for decades and still represents a key element of the therapeutic armamentarium. However, only small increments in survival outcomes have been reached. New clinical trials are designed, including classic chemotherapy in association with either small-molecule inhibitors or mAb. During the past few years, remarkable progress in molecular biology of gastrointestinal noncolorectal cancers, the discovery of specific targets and the resulting development of systemic drugs that block critical kinases and several molecular pathways have all contributed to progress. New biological agents with molecularly targeted therapies are now available or currently included in clinical trials (EGFR inhibitors (i), antiangiogenic agents, c-METi, IDHi, FGFR2i, BRAFi, Pi3Ki/AKTi/mTORi, NTRKi). When we focus on the current state of precision medicine for gastrointestinal malignancies, it becomes apparent that there is a mixed history of success and failure. The aim of this review is to focus on the studies that have been completed to date with target therapies and to understand which of these are currently the accepted choice in clinical practice and which need further confirmation and approval for inclusion in guidelines. All these findings will enable to guide clinical practice for oncologists in the design of the next round of clinical trials.
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13
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Tantau AI, Mandrutiu A, Pop A, Zaharie RD, Crisan D, Preda CM, Tantau M, Mercea V. Extrahepatic cholangiocarcinoma: Current status of endoscopic approach and additional therapies. World J Hepatol 2021; 13:166-186. [PMID: 33708349 PMCID: PMC7934015 DOI: 10.4254/wjh.v13.i2.166] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 12/02/2020] [Accepted: 12/13/2020] [Indexed: 02/06/2023] Open
Abstract
The prognosis of patients with advanced or unresectable extrahepatic cholangiocarcinoma is poor. More than 50% of patients with jaundice are inoperable at the time of first diagnosis. Endoscopic treatment in patients with obstructive jaundice ensures bile duct drainage in preoperative or palliative settings. Relief of symptoms (pain, pruritus, jaundice) and improvement in quality of life are the aims of palliative therapy. Stent implantation by endoscopic retrograde cholangiopancreatography is generally preferred for long-term palliation. There is a vast variety of plastic and metal stents, covered or uncovered. The stent choice depends on the expected length of survival, quality of life, costs and physician expertise. This review will provide the framework for the endoscopic minimally invasive therapy in extrahepatic cholangiocarcinoma. Moreover, additional therapies, such as brachytherapy, photodynamic therapy, radiofrequency ablation, chemotherapy, molecular-targeted therapy and/or immunotherapy by the endoscopic approach, are the nonsurgical methods associated with survival improvement rate and/or local symptom palliation.
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Affiliation(s)
- Alina Ioana Tantau
- Department of Internal Medicine and Gastroenterology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 4 Medical Clinic, Cluj-Napoca 400012, Cluj, Romania
| | - Alina Mandrutiu
- Department of Gastroenterology and Hepatology, Gastroenterology and Hepatology Medical Center, Cluj-Napoca 400132, Cluj, Romania
| | - Anamaria Pop
- Department of Gastroenterology and Hepatology, Gastroenterology and Hepatology Medical Center, Cluj-Napoca 400132, Cluj, Romania
| | - Roxana Delia Zaharie
- Department of Gastroenterology, “Prof. Dr. Octavian Fodor” Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca 400162, Cluj, Romania
- Department of Gastroenterology, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca 400012, Cluj, Romania.
| | - Dana Crisan
- Internal Medicine Department, Cluj-Napoca Internal Medicine Department, “Iuliu Hatieganu” University of Medicine and Pharmacy, 5 Medical Clinic, Cluj-Napoca 400012, Cluj, Romania
| | - Carmen Monica Preda
- Department of Gastroenterology and Hepatology, Clinic Fundeni Institute, “Carol Davila” University of Medicine and Pharmacy, Bucharest 22328, Romania
| | - Marcel Tantau
- Department of Internal Medicine and Gastroenterology, “Prof. Dr. Octavian Fodor” Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca 400162, Cluj, Romania
- Department of Internal Medicine and Gastroenterology, “Iuliu Hatieganu“ University of Medicine and Pharmacy, Cluj-Napoca 400012, Cluj, Romania
| | - Voicu Mercea
- Department of Internal Medicine and Gastroenterology, “Prof. Dr. Octavian Fodor” Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca 400162, Cluj, Romania
- Department of Internal Medicine and Gastroenterology, “Iuliu Hatieganu“ University of Medicine and Pharmacy, Cluj-Napoca 400012, Cluj, Romania
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14
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Wang M, Chen Z, Guo P, Wang Y, Chen G. Therapy for advanced cholangiocarcinoma: Current knowledge and future potential. J Cell Mol Med 2020; 25:618-628. [PMID: 33277810 PMCID: PMC7812297 DOI: 10.1111/jcmm.16151] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 10/21/2020] [Accepted: 11/22/2020] [Indexed: 01/07/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a biliary epithelial tumour that can emerge at any point in the biliary tree. It is commonly classified based on its anatomical site of development into intrahepatic cholangiocarcinoma (ICC), perihilar cholangiocarcinoma (PCC) and distal cholangiocarcinoma (DCC), each of which is associated with varying patient demographics, molecular characteristics and treatment options. CCA patients have poor overall prognoses and 5‐year survival rates. Additionally, CCA is often diagnosed at an advanced stage, with surgical treatment restricted to early‐stage disease. Owing to an increase in the incidence of ICC, that of CCA is also on the rise, with a corresponding increase in the associated mortality, particularly in South America and Asia. Therefore, the development of an effective treatment is crucial to improve the survival of CCA patients. We aimed to systematically review the current understanding of advanced CCA treatment and discuss potential effective strategies.
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Affiliation(s)
- Mingxun Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Ziyan Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Pengyi Guo
- Department of Cardiothoracic Surgery, Ningbo Yinzhou NO.2 Hospital, Ningbo, China
| | - Yi Wang
- Department of Epidemiology and Biostatistics, Public Health and Management School, Wenzhou Medical University, Wenzhou, China
| | - Gang Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
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15
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Personeni N, Lleo A, Pressiani T, Colapietro F, Openshaw MR, Stavraka C, Pouptsis A, Pinato DJ, Rimassa L. Biliary Tract Cancers: Molecular Heterogeneity and New Treatment Options. Cancers (Basel) 2020; 12:3370. [PMID: 33202975 PMCID: PMC7696875 DOI: 10.3390/cancers12113370] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/08/2020] [Accepted: 11/11/2020] [Indexed: 12/13/2022] Open
Abstract
Most patients with biliary tract cancer (BTC) are diagnosed with advanced disease, relapse rates are high in those undergoing surgery and prognosis remains poor, while the incidence is increasing. Treatment options are limited, and chemotherapy is still the standard of care in both adjuvant and advanced disease setting. In recent years, different subtypes of BTC have been defined depending on the anatomical location and genetic and/or epigenetic aberrations. Especially for intrahepatic cholangiocarcinoma (iCCA) novel therapeutic targets have been identified, including fibroblast growth factor receptor 2 gene fusions and isocitrate dehydrogenase 1 and 2 mutations, with molecularly targeted agents having shown evidence of activity in this subgroup of patients. Additionally, other pathways are being evaluated in both iCCA and other subtypes of BTC, alongside targeting of the immune microenvironment. The growing knowledge of BTC biology and molecular heterogeneity has paved the way for the development of new therapeutic approaches that will completely change the treatment paradigm for this disease in the near future. This review provides an overview of the molecular heterogeneity of BTC and summarizes new targets and emerging therapies in development. We also discuss resistance mechanisms, open issues, and future perspectives in the management of BTC.
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Affiliation(s)
- Nicola Personeni
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Rozzano, 20089 Milan, Italy; (N.P.); (T.P.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy; (A.L.); (F.C.)
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy; (A.L.); (F.C.)
- Internal Medicine Center, Humanitas Clinical and Research Center-IRCCS, Rozzano, 20089 Milan, Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Rozzano, 20089 Milan, Italy; (N.P.); (T.P.)
| | - Francesca Colapietro
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy; (A.L.); (F.C.)
- Internal Medicine Center, Humanitas Clinical and Research Center-IRCCS, Rozzano, 20089 Milan, Italy
| | - Mark Robert Openshaw
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London W120HS, UK; (M.R.O.); (D.J.P.)
| | - Chara Stavraka
- Department of Medical Oncology, Guy’s and St Thomas’ NHS Foundation Trust, Great Maze Pond, London SE1 9RT, UK;
| | - Athanasios Pouptsis
- Department of Medical Oncology, “Euromedica” General Clinic, 54645 Thessaloniki, Greece;
| | - David James Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London W120HS, UK; (M.R.O.); (D.J.P.)
| | - Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Rozzano, 20089 Milan, Italy; (N.P.); (T.P.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy; (A.L.); (F.C.)
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16
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Continuum of care for advanced biliary tract cancers. Clin Res Hepatol Gastroenterol 2020; 44:810-824. [PMID: 32586782 DOI: 10.1016/j.clinre.2020.05.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 05/24/2020] [Accepted: 05/27/2020] [Indexed: 02/07/2023]
Abstract
Biliary tract cancers (BTC) are a heterogeneous group of epithelial neoplasms, with a poor prognosis. Advanced BTC remains a challenging, non-curable disease. In this review, we provide an overview of the medical treatment options in advanced BTC and new strategies under development. Gemcitabine plus platinum chemotherapy is the standard first-line therapy in this setting. Recently, 5-fluorouracil, folinic acid plus oxaliplatin (FOLFOX) regimen became the only second-line therapy to be prospectively validated beyond failure of gemcitabine plus cisplatin combination in a phase III study, even though chemotherapy yielded modest survival improvement over best supportive care. Anti-epidermal growth factor receptor and antiangiogenic antibodies have not demonstrated any survival benefit in unselected patient populations. In recent years, knowledge about the molecular heterogeneity of BTC has considerably increased with the advent of large-scale genomic and transcriptomic analyses, opening up new perspectives for so-called personalised targeted therapies. Patients with BTC may be particularly good candidates for biomarker-driven strategies in clinical practice. Among current developments, the targeting of fibroblast growth factor receptor and isocitrate dehydrogenase gene alterations are the most promising avenues, and combination immunotherapies are under investigation.
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17
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Liver Transplantation for Cholangiocarcinoma and Mixed Hepatocellular Cholangiocarcinoma: Working Group Report From the ILTS Transplant Oncology Consensus Conference. Transplantation 2020; 104:1125-1130. [PMID: 32217937 DOI: 10.1097/tp.0000000000003212] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Liver transplantation for cholangiocarcinoma has been an absolute contraindication worldwide due to poor results. However, in recent years and thanks to improvements of patient management and treatments of this cancer, this indication has been revisited. This consensus paper, approved by the International Liver Transplant Society, aims to provide a collection of expert opinions, consensus, and best practices surrounding liver transplantation for cholangiocarcinoma.
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18
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Huang WK, Yeh CN. The Emerging Role of MicroRNAs in Regulating the Drug Response of Cholangiocarcinoma. Biomolecules 2020; 10:biom10101396. [PMID: 33007962 PMCID: PMC7600158 DOI: 10.3390/biom10101396] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 09/22/2020] [Accepted: 09/29/2020] [Indexed: 12/12/2022] Open
Abstract
Cholangiocarcinoma (CCA) is the most common biliary malignancy, and has a poor prognosis. The median overall survival with the standard-of-care chemotherapy (Gemcitabine and cisplatin) in patients with advanced-stage CCA is less than one year. The limited efficacy of chemotherapy or targeted therapy remains a major obstacle to improving survival. The mechanisms involved in drug resistance are complex. Research efforts focusing on the distinct molecular mechanisms underlying drug resistance should prompt the development of treatment strategies that overcome chemoresistance or targeted drug resistance. MicroRNAs (miRNAs) are a class of evolutionarily conserved, short noncoding RNAs regulating gene expression at the post-transcriptional level. Dysregulated miRNAs have been shown to participate in almost all CCA hallmarks, including cell proliferation, migration and invasion, apoptosis, and the epithelial-to-mesenchymal transition. Emerging evidence demonstrates that miRNAs play a role in regulating responses to chemotherapy and targeted therapy. Herein, we present an overview of the current knowledge on the miRNA-mediated regulatory mechanisms underlying drug resistance among CCA. We also discuss the application of miRNA-based therapeutics to CCA, providing the basis for innovative treatment approaches.
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Affiliation(s)
- Wen-Kuan Huang
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan 333, Taiwan;
| | - Chun-Nan Yeh
- Department of Surgery and Liver Research Center, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan 333, Taiwan
- Correspondence: ; Tel.: +886-3281200
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19
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Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, Cardinale V, Carpino G, Andersen JB, Braconi C, Calvisi DF, Perugorria MJ, Fabris L, Boulter L, Macias RIR, Gaudio E, Alvaro D, Gradilone SA, Strazzabosco M, Marzioni M, Coulouarn C, Fouassier L, Raggi C, Invernizzi P, Mertens JC, Moncsek A, Ilyas SI, Heimbach J, Koerkamp BG, Bruix J, Forner A, Bridgewater J, Valle JW, Gores GJ. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol 2020; 17:557-588. [PMID: 32606456 PMCID: PMC7447603 DOI: 10.1038/s41575-020-0310-z] [Citation(s) in RCA: 1481] [Impact Index Per Article: 296.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/29/2020] [Indexed: 02/07/2023]
Abstract
Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree. Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies. The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly. The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary. Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies. In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes. In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments. Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted.
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Affiliation(s)
- Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain.
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
| | - Jose J G Marin
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Shahid A Khan
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Jesper B Andersen
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Chiara Braconi
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Diego F Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
| | - Luca Fabris
- Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy
- Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA
| | - Luke Boulter
- MRC-Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Rocio I R Macias
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Eugenio Gaudio
- Division of Human Anatomy, Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Domenico Alvaro
- Department of Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | | | - Mario Strazzabosco
- Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy
- Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA
| | - Marco Marzioni
- Clinic of Gastroenterology and Hepatology, Universita Politecnica delle Marche, Ancona, Italy
| | | | - Laura Fouassier
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France
| | - Chiara Raggi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center of Autoimmune Liver Diseases, Department of Medicine and Surgery, San Gerardo Hospital, University of Milano, Bicocca, Italy
| | - Joachim C Mertens
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zürich, Switzerland
| | - Anja Moncsek
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zürich, Switzerland
| | - Sumera I. Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | | | | | - Jordi Bruix
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Barcelona Clinic Liver Cancer (BCLC) group, Liver Unit, Hospital Clínic of Barcelona, Fundació Clínic per a la Recerca Biomédica (FCRB), IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Alejandro Forner
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Barcelona Clinic Liver Cancer (BCLC) group, Liver Unit, Hospital Clínic of Barcelona, Fundació Clínic per a la Recerca Biomédica (FCRB), IDIBAPS, University of Barcelona, Barcelona, Spain
| | - John Bridgewater
- Department of Medical Oncology, UCL Cancer Institute, London, UK
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
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Ntanasis-Stathopoulos I, Tsilimigras DI, Gavriatopoulou M, Schizas D, Pawlik TM. Cholangiocarcinoma: investigations into pathway-targeted therapies. Expert Rev Anticancer Ther 2020; 20:765-773. [PMID: 32757962 DOI: 10.1080/14737140.2020.1807333] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Cholangiocarcinoma is a malignant disease of the biliary tract and accounts for 3% of all gastrointestinal tumors. Surgical intervention is currently the only potentially curative strategy for cholangiocarcinoma. For patients with unresectable, advanced or metastatic disease, the combination of gemcitabine with cisplatin is considered the standard treatment. However, currently available therapeutic options have only a marginal benefit, especially among patients with relapsed/refractory tumors. AREAS COVERED We reviewed targeted agents under clinical evaluation for patients with cholangiocarcinoma. FGFR and IDH inhibitors are at the most advanced stage of clinical investigation. EGFR inhibitors have demonstrated contradictory results, whereas inhibition of other molecular pathways, including the RAS/RAF/MEK/ERK, the MET, the PI3K/AKT/mTOR and angiogenetic pathways, has shown minimal or null benefit. EXPERT OPINION Several targeted approaches are being investigated for advanced cholangiocarcinoma. However, randomized clinical trials are needed to define the optimal treatment regimen and address issues including the option of monotherapy or combination regimens, the optimal sequence of different treatments, ways to overcome resistance to targeted treatments, as well as determining the right time and tissue for assessing molecular signatures. Targeted therapies and immunotherapy hold promise for improving patient outcomes in the future.
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Affiliation(s)
- Ioannis Ntanasis-Stathopoulos
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Cente , Columbus, OH, UAS
| | - Diamantis I Tsilimigras
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Cente , Columbus, OH, UAS
| | - Maria Gavriatopoulou
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Alexandra General Hospital , Athens, Greece
| | - Dimitrios Schizas
- Department of Surgery, Laikon University Hospital, National and Kapodistrian University of Athens , Athens, Greece
| | - Timothy M Pawlik
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Alexandra General Hospital , Athens, Greece
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21
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Lamarca A, Ross P, Wasan HS, Hubner RA, McNamara MG, Lopes A, Manoharan P, Palmer D, Bridgewater J, Valle JW. Advanced Intrahepatic Cholangiocarcinoma: Post Hoc Analysis of the ABC-01, -02, and -03 Clinical Trials. J Natl Cancer Inst 2020; 112:200-210. [PMID: 31077311 DOI: 10.1093/jnci/djz071] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 03/26/2019] [Accepted: 03/19/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The incidence of intrahepatic cholangiocarcinoma (iCCA) is increasing. The aim of the study was to provide reference survival data for patients with advanced iCCA treated with first-line cisplatin-gemcitabine chemotherapy (current standard of care). METHODS Individual data from patients with iCCA recruited into the prospective, random assignment Advanced Biliary Tract Cancer (ABC)-01, -02, and -03 studies were retrieved. The prevalence and survival of liver-only iCCA was also assessed. Survival analysis was performed using univariate and multivariable Cox regression. All statistical tests were two-sided. RESULTS Of 534 patients recruited into the ABC-01, -02, and -03 studies, 109 (20.4%) had iCCA. Most patients (n = 86, 78.9%) had metastatic disease at the time of recruitment; 52 patients (47.7%) had liver-only disease. Following random assignment, 66 (60.6%) iCCA patients received cisplatin and gemcitabine. The median progression-free and overall survival (OS) were 8.4 months (95% confidence interval [CI] = 5.9 to 8.9 months) and 15.4 months (95% CI = 11.1 to 17.9 months), respectively. Of these 66 patients, 34 patients (51.5%) had liver-only disease. Following chemotherapy, 30 (45.5%) and 21 (31.8%) were progression-free at 3 and 6 months from chemotherapy commencement, respectively. The median OS for patients with liver-only iCCA at diagnosis and after 3 and 6 months of chemotherapy was 16.7 months (95% CI = 8.7 to 20.2 months), 17.9 months (95% CI = 11.7 to 20.9 months), and 18.9 months (95% CI = 16.7 to 25.9 months), respectively. Multivariable analysis confirmed that iCCA had a longer OS compared with other non-iCCA biliary tract cancers (hazard ratio = 0.58, 95% CI = 0.35 to 0.95, P value = .03); liver-only iCCA patients also showed longer OS even though findings did not reach statistical significance (hazard ratio = 0.65, 95% CI = 0.36 to 1.19, P value = .16). CONCLUSIONS Patients diagnosed with advanced iCCA have a better OS compared with other biliary tract cancers; a similar trend was identified for patients diagnosed with liver-only iCCA. These findings are to be considered for future clinical trial design.
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Affiliation(s)
- Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.,Division of Cancer Sciences, University of Manchester, Manchester, UK.,Cancer Research UK & UCL Cancer Centre, University College of London, London, UK
| | - Paul Ross
- Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Harpreet S Wasan
- Department of Medical Oncology, Imperial College Healthcare, London, UK
| | - Richard A Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.,Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Mairéad G McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.,Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Andre Lopes
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.,Division of Cancer Sciences, University of Manchester, Manchester, UK.,Cancer Research UK & UCL Cancer Centre, University College of London, London, UK
| | - Prakash Manoharan
- Department of Radiology and Nuclear Medicine, The Christie NHS Foundation Trust, Manchester, UK
| | - Daniel Palmer
- Department of Medical Oncology, Clatterbridge Cancer Centre, Liverpool, UK
| | - John Bridgewater
- Department of Medical Oncology, UCL Cancer Institute, London, UK
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.,Division of Cancer Sciences, University of Manchester, Manchester, UK
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22
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Montal R, Sia D, Montironi C, Leow WQ, Esteban-Fabró R, Pinyol R, Torres-Martin M, Bassaganyas L, Moeini A, Peix J, Cabellos L, Maeda M, Villacorta-Martin C, Tabrizian P, Rodriguez-Carunchio L, Castellano G, Sempoux C, Minguez B, Pawlik TM, Labgaa I, Roberts LR, Sole M, Fiel MI, Thung S, Fuster J, Roayaie S, Villanueva A, Schwartz M, Llovet JM. Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma. J Hepatol 2020; 73:315-327. [PMID: 32173382 PMCID: PMC8418904 DOI: 10.1016/j.jhep.2020.03.008] [Citation(s) in RCA: 174] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 03/04/2020] [Accepted: 03/04/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Cholangiocarcinoma (CCA), a deadly malignancy of the bile ducts, can be classified based on its anatomical location into either intrahepatic (iCCA) or extrahepatic (eCCA), each with different pathogenesis and clinical management. There is limited understanding of the molecular landscape of eCCA and no targeted therapy with clinical efficacy has been approved. We aimed to provide a molecular classification of eCCA and identify potential targets for molecular therapies. METHODS An integrative genomic analysis of an international multicenter cohort of 189 eCCA cases was conducted. Genomic analysis included whole-genome expression, targeted DNA-sequencing and immunohistochemistry. Molecular findings were validated in an external set of 181 biliary tract tumors from the ICGC. RESULTS KRAS (36.7%), TP53 (34.7%), ARID1A (14%) and SMAD4 (10.7%) were the most prevalent mutations, with ∼25% of tumors having a putative actionable genomic alteration according to OncoKB. Transcriptome-based unsupervised clustering helped us define 4 molecular classes of eCCA. Tumors classified within the Metabolic class (19%) showed a hepatocyte-like phenotype with activation of the transcription factor HNF4A and enrichment in gene signatures related to bile acid metabolism. The Proliferation class (23%), more common in patients with distal CCA, was characterized by enrichment of MYC targets, ERBB2 mutations/amplifications and activation of mTOR signaling. The Mesenchymal class (47%) was defined by signatures of epithelial-mesenchymal transition, aberrant TGFβ signaling and poor overall survival. Finally, tumors in the Immune class (11%) had a higher lymphocyte infiltration, overexpression of PD-1/PD-L1 and molecular features associated with a better response to immune checkpoint inhibitors. CONCLUSION An integrative molecular characterization identified distinct subclasses of eCCA. Genomic traits of each class provide the rationale for exploring patient stratification and novel therapeutic approaches. LAY SUMMARY Targeted therapies have not been approved for the treatment of extrahepatic cholangiocarcinoma. We performed a multi-platform molecular characterization of this tumor in a cohort of 189 patients. These analyses revealed 4 novel transcriptome-based molecular classes of extrahepatic cholangiocarcinoma and identified ∼25% of tumors with actionable genomic alterations, which has potential prognostic and therapeutic implications.
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Affiliation(s)
- Robert Montal
- Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain; Gastrointestinal Unit, Medical Oncology Department, ICMHO, Hospital Clínic, Barcelona, Catalonia, Spain
| | - Daniela Sia
- Liver Cancer Program, Divisions of Liver Diseases, Pathology Department and RM Transplant Institute, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Carla Montironi
- Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
| | - Wei Q Leow
- Liver Cancer Program, Divisions of Liver Diseases, Pathology Department and RM Transplant Institute, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Anatomical Pathology, Singapore General Hospital, Duke-NUS Medical School, Singapore
| | - Roger Esteban-Fabró
- Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
| | - Roser Pinyol
- Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
| | - Miguel Torres-Martin
- Liver Cancer Program, Divisions of Liver Diseases, Pathology Department and RM Transplant Institute, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Laia Bassaganyas
- Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
| | - Agrin Moeini
- Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
| | - Judit Peix
- Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
| | - Laia Cabellos
- Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
| | - Miho Maeda
- Liver Cancer Program, Divisions of Liver Diseases, Pathology Department and RM Transplant Institute, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Carlos Villacorta-Martin
- Liver Cancer Program, Divisions of Liver Diseases, Pathology Department and RM Transplant Institute, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Parissa Tabrizian
- Liver Cancer Program, Divisions of Liver Diseases, Pathology Department and RM Transplant Institute, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | | | | | - Christine Sempoux
- Service of Clinical Pathology, Institute of Pathology, Lausanne University Hospital CHUV, Lausanne, Switzerland
| | - Beatriz Minguez
- Liver Unit, Department of Internal Medicine, Vall d'Hebron University Hospital, Vall d'Hebron Institut of Research, Center for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Autonomous University of Barcelona, Barcelona, Spain
| | - Timothy M Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Ismail Labgaa
- Department of Visceral Surgery, Lausanne University Hospital CHUV, Lausanne, Switzerland
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Manel Sole
- Pathology Department, IDIBAPS-Hospital Clinic Barcelona, University of Barcelona, Catalonia, Spain
| | - Maria I Fiel
- Liver Cancer Program, Divisions of Liver Diseases, Pathology Department and RM Transplant Institute, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Swan Thung
- Liver Cancer Program, Divisions of Liver Diseases, Pathology Department and RM Transplant Institute, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Josep Fuster
- Hepatobiliary and Pancreatic Surgery Department, IDIBAPS-Hospital Clinic Barcelona, University of Barcelona, Catalonia, Spain
| | - Sasan Roayaie
- Department of Surgery, White Plains Hospital, White Plains, New York, USA; Division of Hepatobiliary Surgery, Lenox Hill Hospital, New York, New York, USA
| | - Augusto Villanueva
- Liver Cancer Program, Divisions of Liver Diseases, Pathology Department and RM Transplant Institute, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Myron Schwartz
- Liver Cancer Program, Divisions of Liver Diseases, Pathology Department and RM Transplant Institute, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Josep M Llovet
- Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain; Liver Cancer Program, Divisions of Liver Diseases, Pathology Department and RM Transplant Institute, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
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Zheng T, Jin J, Zhou L, Zhang Y. Comparison between Fluoropyrimidine-Cisplatin and Gemcitabine-Cisplatin as First-Line Chemotherapy for Advanced Biliary Tract Cancer: A Meta-Analysis. Oncol Res Treat 2020; 43:460-469. [PMID: 32629449 DOI: 10.1159/000507093] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Accepted: 03/09/2020] [Indexed: 01/07/2023]
Abstract
BACKGROUND Gemcitabine-cisplatin (GP) has been regarded as standard first-line chemotherapy for advanced biliary tract cancer (BTC). Fluoropyrimidine-cisplatin (FP) has also shown a survival benefit. However, the clinical choice between them is controversial. METHODS We performed a meta-analysis to assess the efficacy and safety of the two chemotherapy regimens. RESULTS A total of 5 studies (2 randomized controlled trials, RCTs, and 3 retrospective studies) involving 727 patients were included. There were no statistically significant differences between the two groups in overall response rate, ORR (risk ratio, RR = 1.13, 95% confidence interval, CI, 0.80-1.58, p = 0.489), disease control rate, DCR (RR = 1.02, 95% CI 0.91-1.13, p = 0.751), progression-free survival/time to progression (hazard rate, HR = 0.95, 95% CI 0.86-1.05, p = 0.315) and overall survival (HR = 1.06, 95% CI 0.98-1.14, p = 0.125). As compared with GP, FP showed lower incidences of all grade 3/4 adverse events with statistical significance (p < 0.001). In a subgroup analysis of RCTs, no statistical differences were found between FP and GP in ORR (RR = 1.06; 95% CI 0.58-1.95; p = 0.842) and DCR (RR = 1.22; 95% CI 1.00-1.50; p = 0.056), but FP showed significantly lower incidences of all grade 3/4 adverse events compared with GP (p < 0.01). Some limitations of the meta-analysis are retrospective studies included, some end points within the trials missing rendering a pooled analysis of the two RCTs impossible and heterogeneous fluoropyrimidine combinations. All studies were performed in Asia which are not completely transferable to European patients. CONCLUSION With some limitations, the meta-analysis suggested that FP seems to be as effective as GP with a more favorable safety profile in first-line chemotherapy for Asian patients with advanced BTC.
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Affiliation(s)
- Ting Zheng
- Department of Oncology, The First People's Hospital of Yuhang District, Hangzhou, China
| | - Jianjiang Jin
- Department of Oncology, The First People's Hospital of Yuhang District, Hangzhou, China
| | - Li Zhou
- Department of Oncology, The First People's Hospital of Yuhang District, Hangzhou, China,
| | - Yuefeng Zhang
- Department of Hematology, The First People's Hospital of Yuhang District, Hangzhou, China
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24
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Mizrahi JD, Shroff RT. New Treatment Options for Advanced Biliary Tract Cancer. Curr Treat Options Oncol 2020; 21:63. [DOI: 10.1007/s11864-020-00767-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Li X, Gao L, Zhang L, Sun H, Gou H. Third-line sunitinib treatment in a VHL-mutated metastatic intrahepatic cholangiocarcinoma: a case report and literature review. Cancer Biol Ther 2020; 21:785-789. [PMID: 32552305 DOI: 10.1080/15384047.2020.1769418] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive malignancy with a poor prognosis. There is no standard treatment beyond first-line chemotherapy and no molecular-targeted drug approved for advanced iCCA. We herein present a case of a 46-y-old Asian iCCA patient with multiple metastases in lung, bone, and liver. The patient progressed rapidly after first- and second-line chemotherapy. According to next-generation sequencing result of somatic Von Hippel-Lindau (VHL) gene mutation, the patient was administered third-line sunitinib and obtained a relatively longer survival of 9 months after taking sunitinib. Additionally, we briefly summarized the current targeted treatment of iCCA. To our knowledge, this is the first report of VHL mutation and sunitinib usage in metastatic iCCA patient. As a highly heterogeneous and aggressive malignancy, we strongly recommend making clinical decisions based on precision medicine concept in advanced iCCA.
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Affiliation(s)
- Xiaofen Li
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Limin Gao
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Li Zhang
- Department of Oncology, Pengzhou People's Hospital, Pengzhou, P.R. China
| | - Hongna Sun
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Hongfeng Gou
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, P.R. China
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26
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Sadeghi S, Bejjani A, Finn RS. Systemic Therapy for Primary Liver Tumors: Cholangiocarcinoma and Hepatocellular Carcinoma. Surg Oncol Clin N Am 2020; 28:695-715. [PMID: 31472914 DOI: 10.1016/j.soc.2019.06.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
In the past decade, there has been significant progress in the treatment of primary liver cancer. There has been increasing knowledge of the molecular alterations occurring in these tumors, which is now being translated into patient care. Ongoing clinical trials will further advance the therapeutic options available to patients, including the introduction of molecular targeted therapeutics and immunotherapy approaches. Critical to the success of these new drugs, is the appropriate use of them in the clinic to maximize efficacy and limit toxicity.
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Affiliation(s)
- Saeed Sadeghi
- UCLA Oncology, 2020 Santa Monica Blvd, Suite 230, Santa Monica, CA 90404, USA
| | - Anthony Bejjani
- UCLA Oncology, 2825 Santa Monica Blvd, Suite 200, Santa Monica, CA 90404, USA
| | - Richard S Finn
- UCLA Oncology, 2825 Santa Monica Blvd, Suite 200, Santa Monica, CA 90404, USA.
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D'Andrea MR, Gill CM, Umphlett M, Tsankova NM, Fowkes M, Bederson JB, Brastianos PK, Shrivastava RK. Brain Metastases from Biliary Tract Cancers: A Case Series and Review of the Literature in the Genomic Era. Oncologist 2020; 25:447-453. [PMID: 31694894 PMCID: PMC7216433 DOI: 10.1634/theoncologist.2019-0306] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 09/12/2019] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Biliary tract cancers (BTCs) are highly fatal malignancies that make up less than 1% of all cancers. BTC is often diagnosed at an unresectable stage; surgical resection remains the only definitive treatment. Brain metastases (BMs) from BTC are extremely rare, and few studies on patients with BMs from BTC exist. The aim of this study was to identify clinical characteristics associated with poor prognosis for patients with BMs from BTC. MATERIALS AND METHODS We performed a retrospective review of electronic medical records for patients with BMs from BTC managed at Mount Sinai Hospital from 2000 to 2017. Data on patient characteristics, magnetic resonance imaging findings, treatment regimens, and clinical outcomes were analyzed. RESULTS We identified 1,910 patients with BTC. Nine patients developed BMs, with an incidence of 0.47%. Of these nine patients, six had intrahepatic cholangiocarcinoma, two had extrahepatic cholangiocarcinoma, and one had gallbladder cancer. Six (66.7%) patients had one BM, one (11.1%) patient had two BMs, and two (22.2%) patients had three or more BMs. Four (44.4%) patients underwent BM resection, and seven (77.8%) received BM radiation. Median overall survival from time of BM diagnosis was 3.8 months (95% confidence interval 0.1-16.9). CONCLUSION Development of BMs from BTC is rare; however, prognosis is less than 4 months. BM diagnosis can occur within 2 years of primary diagnosis. As targeted therapeutics emerge, future studies ought to focus on identifying genomic BM markers associated with BTC subtypes. IMPLICATIONS FOR PRACTICE In the largest retrospective study of biliary tract cancer brain metastases, the clinical presentation and outcomes are reported of nine patients with an extremely rare clinical entity. The genomic literature and potential therapeutic targets for these patients with limited treatment options is comprehensively and exhaustively discussed.
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Affiliation(s)
- Megan R. D'Andrea
- Department of Neurosurgery, Mount Sinai Medical CenterNew YorkNew YorkUSA
| | - Corey M. Gill
- Department of Neurosurgery, Mount Sinai Medical CenterNew YorkNew YorkUSA
| | - Melissa Umphlett
- Department of Pathology, Mount Sinai Medical CenterNew YorkNew YorkUSA
| | | | - Mary Fowkes
- Department of Pathology, Mount Sinai Medical CenterNew YorkNew YorkUSA
| | - Joshua B. Bederson
- Department of Neurosurgery, Mount Sinai Medical CenterNew YorkNew YorkUSA
| | - Priscilla K. Brastianos
- Department of Neurology and Cancer Center, Massachusetts General HospitalBostonMassachusettsUSA
| | - Raj K. Shrivastava
- Department of Neurosurgery, Mount Sinai Medical CenterNew YorkNew YorkUSA
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Conci S, Ruzzenente A, Simbolo M, Bagante F, Rusev B, Isa G, Lawlor RT, Pedrazzani C, Iacono C, Guglielmi A, Scarpa A. Multigene mutational profiling of biliary tract cancer is related to the pattern of recurrence in surgically resected patients. Updates Surg 2020; 72:119-128. [PMID: 32020551 DOI: 10.1007/s13304-020-00718-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 01/26/2020] [Indexed: 01/04/2023]
Abstract
The aim of the present study was to investigate the relationship between the mutational gene profile and recurrence in biliary tract cancers (BTC). A total of 103 specimens of patients with BTC, who underwent curative surgery in a single tertiary HPB surgery referral center from 1990 to 2012, were assessed for mutational status in 52 cancer-related genes. Considering the different types of BTC, the 5-year recurrence-free survival (RFS) rate was 16.7% (median RFS 7 months) in gallbladder cancer, 42.9% (median RFS 26.4 months) in intrahepatic cholangiocarcinoma, and 19.7% (median RFS 16.5 months) in perihilar cholangiocarcinoma, p = 0.166. At the multivariate analysis including clinical, pathological, and molecular features, the factors independently related to RFS were radicality of surgery (OR 2.050, CI 1.104-3.807, p = 0.023), LN status (OR 1.835, CI 1.006-3.348, p = 0.048), mutational status of ARID1A (OR 2.566, CI 1.174-5.608, p = 0.018), and TP53 (OR 2.805, CI 4.432-5.496, p = 0.003). ARID1A mutation was associated with a local and systemic recurrence in the 43% and 29% of cases, respectively; and TP53 mutation was associated with a local and systemic recurrence in the 29% and 41% of cases. Moreover, TP53 was most commonly mutated in tumor of patients with early recurrence, p = 0.044. ARID1A and TP53 mutations seem to be related to poor outcome after surgery and may be considered molecular predictors of the biological aggressiveness in BTC.
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Affiliation(s)
- Simone Conci
- Division of General and Hepatobiliary Surgery, Department of Surgery, University of Verona Medical School, G.B. Rossi University Hospital, Piazzale L.A. Scuro, 10, 37134, Verona, Italy.
| | - Andrea Ruzzenente
- Division of General and Hepatobiliary Surgery, Department of Surgery, University of Verona Medical School, G.B. Rossi University Hospital, Piazzale L.A. Scuro, 10, 37134, Verona, Italy
| | - Michele Simbolo
- ARC-Net Research Centre, University of Verona, University Hospital G.B. Rossi, 37134, Verona, Italy
- Department of Pathology and Diagnostics, University of Verona, University Hospital G.B. Rossi, 37134, Verona, Italy
| | - Fabio Bagante
- Division of General and Hepatobiliary Surgery, Department of Surgery, University of Verona Medical School, G.B. Rossi University Hospital, Piazzale L.A. Scuro, 10, 37134, Verona, Italy
| | - Borislav Rusev
- ARC-Net Research Centre, University of Verona, University Hospital G.B. Rossi, 37134, Verona, Italy
- Department of Pathology and Diagnostics, University of Verona, University Hospital G.B. Rossi, 37134, Verona, Italy
| | - Giulia Isa
- Division of General and Hepatobiliary Surgery, Department of Surgery, University of Verona Medical School, G.B. Rossi University Hospital, Piazzale L.A. Scuro, 10, 37134, Verona, Italy
| | - Rita T Lawlor
- ARC-Net Research Centre, University of Verona, University Hospital G.B. Rossi, 37134, Verona, Italy
- Department of Pathology and Diagnostics, University of Verona, University Hospital G.B. Rossi, 37134, Verona, Italy
| | - Corrado Pedrazzani
- Division of General and Hepatobiliary Surgery, Department of Surgery, University of Verona Medical School, G.B. Rossi University Hospital, Piazzale L.A. Scuro, 10, 37134, Verona, Italy
| | - Calogero Iacono
- Division of General and Hepatobiliary Surgery, Department of Surgery, University of Verona Medical School, G.B. Rossi University Hospital, Piazzale L.A. Scuro, 10, 37134, Verona, Italy
| | - Alfredo Guglielmi
- Division of General and Hepatobiliary Surgery, Department of Surgery, University of Verona Medical School, G.B. Rossi University Hospital, Piazzale L.A. Scuro, 10, 37134, Verona, Italy
| | - Aldo Scarpa
- ARC-Net Research Centre, University of Verona, University Hospital G.B. Rossi, 37134, Verona, Italy
- Department of Pathology and Diagnostics, University of Verona, University Hospital G.B. Rossi, 37134, Verona, Italy
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Abstract
PURPOSE OF REVIEW To review new treatment and advances in biliary tract cancer (BTC). RECENT FINDINGS In the prespecified per-protocol analysis of the randomized phase III trial BILCAP, adjuvant capecitabine offers overall survival (OS) benefit when compared with observation with statistical significance. In the first-line setting in metastatic BTC, gemcitabine and S-1 had noninferior OS compared with gemcitabine and cisplatin. In a separate phase III study, the triplet of gemcitabine, cisplatin and S-1 (GCS) had superior OS compared with standard gemcitabine and cisplatin. The regimen of modified FOLFOX (fluorouracil, leucovorin and oxaliplatin) regimen can be considered a potential standard option in the second-line setting for patients who failed first-line therapy with gemcitabine-based regimens. Trials in genomically selected patients indicate activity of fibroblast growth factor receptor inhibitors, mutant isocitrate dehydrogenase inhibitors and immune checkpoint inhibitors. SUMMARY Capecitabine is a new option for adjuvant treatment in resected BTC. In the metastatic setting, gemcitabine and S-1 or GCS are new options for first-line therapy and modified FOLFOX regimen should be considered as a potential new empirical standard of care in genomically agnostic patients requiring second-line therapy. Future randomized trials will evaluate the role of targeted agents and immunotherapy in advanced BTC, both in monotherapy and in combination.
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Capece D, Verzella D, Di Francesco B, Alesse E, Franzoso G, Zazzeroni F. NF-κB and mitochondria cross paths in cancer: mitochondrial metabolism and beyond. Semin Cell Dev Biol 2020; 98:118-128. [PMID: 31132468 DOI: 10.1016/j.semcdb.2019.05.021] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 05/21/2019] [Accepted: 05/22/2019] [Indexed: 12/13/2022]
Abstract
NF-κB plays a pivotal role in oncogenesis. This transcription factor is best known for promoting cancer cell survival and tumour-driving inflammation. However, several lines of evidence support a crucial role for NF-κB in governing energy homeostasis and mediating cancer metabolic reprogramming. Mitochondria are central players in many metabolic processes altered in cancer. Beyond their bioenergetic activity, several facets of mitochondria biology, including mitochondrial dynamics and oxidative stress, promote and sustain malignant transformation. Recent reports revealed an intimate connection between NF-κB pathway and the oncogenic mitochondrial functions. NF-κB can impact mitochondrial respiration and mitochondrial dynamics, and, reciprocally, mitochondria can sense stress signals and convert them into cell biological responses leading to NF-κB activation. In this review we discuss their emerging reciprocal regulation and the significance of this interplay for anticancer therapy.
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Affiliation(s)
- Daria Capece
- Centre for Cell Signalling and Inflammation, Department of Medicine, Imperial College London, W12 0NN London, UK.
| | - Daniela Verzella
- Centre for Cell Signalling and Inflammation, Department of Medicine, Imperial College London, W12 0NN London, UK.
| | - Barbara Di Francesco
- Department of Biotechnological and Applied Clinical Sciences (DISCAB), University of L'Aquila, 67100, L'Aquila, Italy.
| | - Edoardo Alesse
- Department of Biotechnological and Applied Clinical Sciences (DISCAB), University of L'Aquila, 67100, L'Aquila, Italy.
| | - Guido Franzoso
- Centre for Cell Signalling and Inflammation, Department of Medicine, Imperial College London, W12 0NN London, UK.
| | - Francesca Zazzeroni
- Department of Biotechnological and Applied Clinical Sciences (DISCAB), University of L'Aquila, 67100, L'Aquila, Italy.
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Abstract
Cholangiocellular carcinoma (CCA) is one of the primary liver tumors and overall represents a rare malignancy; however, in recent years the incidence, particularly of intrahepatic CCA (iCCA) has increased worldwide. Due to the high mortality, CCAs cause a significant proportion of cancer-related deaths also in Germany. Because the diagnosis is often made in advanced stages of the disease, in many cases a surgical approach with curative intention is not possible. For locally advanced or metastatic CCA the combination of gemcitabine and cisplatin currently remains the only approved systemic treatment. As the average survival time is only approximately 12 months even under first-line treatment with gemcitabine/cisplatin, research is focused on developing new molecularly targeted and immunological treatment options. Various studies are currently being carried out to investigate approval options for targeted treatment, which could be considered for genetically altered tumors, e.g. in fibroblast growth factor receptor (FGFR) fusion and isocitrate dehydrogenase (IDH) mutations. Additionally, initial clinical data on immune checkpoint inhibitors are available for CCA. Due to the complex selection and partially limited applicability of current treatment options in patients with CCA, an early collaboration with a gastroenterology and oncology center with the possibility of supervision by a tumor board consisting of gastroenterological oncologists, surgeons, radiologists and radio-oncologists or in advanced stages by a molecular tumor board is essential.
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Mizrahi JD, Gunchick V, Mody K, Xiao L, Surapaneni P, Shroff RT, Sahai V. Multi-institutional retrospective analysis of FOLFIRI in patients with advanced biliary tract cancers. World J Gastrointest Oncol 2020; 12:83-91. [PMID: 31966916 PMCID: PMC6960075 DOI: 10.4251/wjgo.v12.i1.83] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 08/09/2019] [Accepted: 09/13/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Gemcitabine plus platinum is the standard of care first-line treatment for advanced biliary tract cancers (BTC). There is no established second-line therapy, and retrospective reviews report median progression-free survival (PFS) less than 3 mo on second-line therapy. 5-Fluorouracil plus irinotecan (FOLFIRI) is a commonly used regimen in patients with BTC who have progressed on gemcitabine plus platinum, though there is a paucity of data regarding its efficacy in this population.
AIM To assess the efficacy of FOLFIRI in patients with biliary tract cancers.
METHODS We retrospectively identified patients with advanced BTC who were treated with FOLFIRI at MD Anderson, University of Michigan and Mayo Clinic in Jacksonville. Data were collected on patient demographics, BTC subtype, response per RECIST v1.1, progression and survival.
RESULTS Ninety-eight patients were included of which 74 (75%) had metastatic and 24 (25%) had locally advanced disease at the time of treatment with FOLFIRI. The median age was 60 (range, 22-86) years. The number of patients with extrahepatic cholangiocarcinoma, gall bladder cancer and intrahepatic cholangiocarcinoma were 10, 17 and 71, respectively. FOLFIRI was used as 1st, 2nd, 3rd or 4th – Nth lines in 8, 50, 36 and 4 patients, respectively. Median duration on FOLFIRI in the entire cohort was 2.2 (range, 0.5-8.4) mo. The median PFS and overall survival were 2.4 (95% confidence interval (CI): 1.7-3.1) and 6.6 (95%CI: 4.7-8.4) mo, respectively. Median PFS for patients treated with FOLFIRI in 1st, 2nd, 3rd or 4th – Nth lines were 3.1, 2.5, 2.3 and 1.5 mo, respectively. Eighteen patients received concurrent bevacizumab (n = 13) or EGFR-targeted therapy (n = 5) with FOLFIRI, with a median PFS of 2.7 mo (95%CI: 1.7-5.1).
CONCLUSION In this largest multi-institution retrospective review of 98 patients with BTC treated with FOLFIRI, efficacy appears to be modest with outcomes similar to other cytotoxic chemotherapy regimens.
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Affiliation(s)
- Jonathan D Mizrahi
- Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77005, United States
| | - Valerie Gunchick
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, United States
| | - Kabir Mody
- Division of Medical Oncology, Mayo Clinic Cancer Center, Jacksonville, FL 32224, United States
| | - Lianchun Xiao
- Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77005, United States
| | - Phanikeerthi Surapaneni
- Division of Medical Oncology, Mayo Clinic Cancer Center, Jacksonville, FL 32224, United States
| | - Rachna T Shroff
- University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, United States
| | - Vaibhav Sahai
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, United States
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33
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Mizrahi JD, Gunchick V, Mody K, Xiao L, Surapaneni P, Shroff RT, Sahai V. Multi-institutional retrospective analysis of FOLFIRI in patients with advanced biliary tract cancers. World J Gastrointest Oncol 2020. [DOI: 10.4251/wjgo.v12.i11.83] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
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Abstract
AbstractChondrosarcomas are rare cancers of bone that arise from the malignant transformation of cells of chondrocytic lineage. They are known to be resistant to systemic cytotoxic chemotherapy and radiotherapy. The mainstay of management of localised disease is en bloc surgical resection with curative intent. Metastatic chondrosarcoma has a dismal prognosis, and to date, there are no proven effective systemic therapies in the advanced setting. Genomic studies have demonstrated that 50 to 80% of chondrosarcomas harbour a mutation in either the IDH1 or IDH2 gene. IDH inhibitors are currently under investigation in clinical trials, after showing promising results in phase 1 studies in IDH mutated cancers. In chondrosarcoma, IDH mutations represent an attractive target, however, early results with IDH inhibitors in IDH mutated chondrosarcoma are modest and the final results of ongoing trials are eagerly awaited.
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35
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Turkes F, Carmichael J, Cunningham D, Starling N. Contemporary Tailored Oncology Treatment of Biliary Tract Cancers. Gastroenterol Res Pract 2019; 2019:7698786. [PMID: 31929787 PMCID: PMC6935796 DOI: 10.1155/2019/7698786] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 09/05/2019] [Indexed: 02/06/2023] Open
Abstract
Biliary tract cancers (BTCs) are poor prognosis malignancies with limited treatment options. Capecitabine has recently emerged as an effective agent in the adjuvant setting; however, treatment of advanced disease is still limited to first-line cisplatin and gemcitabine chemotherapy. Recent global efforts in genomic profiling and molecular subtyping of BTCs have uncovered a wealth of genomic aberrations which may carry prognostic significance and/or predict response to treatment, and several targeted agents have shown promising results in clinical trials. As such, the uptake of comprehensive genomic profiling for patients with BTCs and the expansion of basket trials to include these patients are growing. This review describes the currently approved systemic therapies for BTCs and provides insight into the emerging targeted and immunotherapeutic agents, as well as conventional chemotherapeutic regimes, currently being investigated in clinical trials.
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Affiliation(s)
- Fiona Turkes
- Department of Medicine, Royal Marsden Hospital NHS Foundation Trust, London, UK
| | - Juliet Carmichael
- Department of Medicine, Royal Marsden Hospital NHS Foundation Trust, London, UK
| | - David Cunningham
- Department of Medicine, Royal Marsden Hospital NHS Foundation Trust, London, UK
| | - Naureen Starling
- Department of Medicine, Royal Marsden Hospital NHS Foundation Trust, London, UK
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36
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Bridgewater J. Systemic treatment of biliary tract cancer: now we have the evidence. Ann Oncol 2019; 30:1851-1852. [PMID: 31638143 DOI: 10.1093/annonc/mdz441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/09/2023] Open
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Lau DK, Mouradov D, Wasenang W, Luk IY, Scott CM, Williams DS, Yeung YH, Limpaiboon T, Iatropoulos GF, Jenkins LJ, Reehorst CM, Chionh F, Nikfarjam M, Croagh D, Dhillon AS, Weickhardt AJ, Muramatsu T, Saito Y, Tebbutt NC, Sieber OM, Mariadason JM. Genomic Profiling of Biliary Tract Cancer Cell Lines Reveals Molecular Subtypes and Actionable Drug Targets. iScience 2019; 21:624-637. [PMID: 31731200 PMCID: PMC6889747 DOI: 10.1016/j.isci.2019.10.044] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/21/2019] [Accepted: 10/22/2019] [Indexed: 01/07/2023] Open
Abstract
Biliary tract cancers (BTCs) currently have no approved targeted therapies. Although genomic profiling of primary BTCs has identified multiple potential drug targets, accurate models are needed for their evaluation. Genomic profiling of 22 BTC cell lines revealed they harbor similar mutational signatures, recurrently mutated genes, and genomic alterations to primary tumors. Transcriptomic profiling identified two major subtypes, enriched for epithelial and mesenchymal genes, which were also evident in patient-derived organoids and primary tumors. Interrogating these models revealed multiple mechanisms of MAPK signaling activation in BTC, including co-occurrence of low-activity BRAF and MEK mutations with receptor tyrosine kinase overexpression. Finally, BTC cell lines with altered ERBB2 or FGFRs were exquisitely sensitive to specific targeted agents, whereas surprisingly, IDH1-mutant lines did not respond to IDH1 inhibitors in vitro. These findings establish BTC cell lines as robust models of primary disease, reveal specific molecular disease subsets, and highlight specific molecular vulnerabilities in these cancers.
BTC cell lines harbor similar genomic alterations to primary tumors Transcriptomic profiling of BTC cell lines identified two molecular subtypes MAPK signaling is activated in BTC via multiple mechanisms BTC lines with deregulated ERBB2 or FGFRs respond to specific targeted therapies
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Affiliation(s)
- David K Lau
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
| | - Dmitri Mouradov
- Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia
| | - Wiphawan Wasenang
- School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia; Centre for Research and Development of Medical Diagnostic Laboratories, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Ian Y Luk
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
| | - Cameron M Scott
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia
| | - David S Williams
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
| | - Yvonne H Yeung
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia
| | - Temduang Limpaiboon
- Centre for Research and Development of Medical Diagnostic Laboratories, Khon Kaen University, Khon Kaen 40002, Thailand
| | - George F Iatropoulos
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
| | - Laura J Jenkins
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
| | - Camilla M Reehorst
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
| | - Fiona Chionh
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia
| | - Mehrdad Nikfarjam
- Department of Surgery, University of Melbourne, Melbourne, VIC 3084, Australia
| | - Daniel Croagh
- Department of Surgery, Monash Medical Centre, Monash University, Melbourne, VIC 3168, Australia
| | - Amardeep S Dhillon
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Medicine, Deakin University, Geelong, VIC 3216, Australia
| | - Andrew J Weickhardt
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
| | - Toshihide Muramatsu
- Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, Tokyo 105-8512, Japan
| | - Yoshimasa Saito
- Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, Tokyo 105-8512, Japan
| | - Niall C Tebbutt
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
| | - Oliver M Sieber
- Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia; Department of Surgery, University of Melbourne, Melbourne, VIC 3084, Australia; Department of Biochemistry & Molecular Biology, Monash University, Melbourne, VIC 3800, Australia; Department of Medicine, The University of Melbourne, Melbourne, VIC 3052, Australia
| | - John M Mariadason
- Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia; Department of Medicine, The University of Melbourne, Melbourne, VIC 3052, Australia.
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Chae H, Kim D, Yoo C, Kim KP, Jeong JH, Chang HM, Lee SS, Park DH, Song TJ, Hwang S, Kim KH, Song GW, Ahn CS, Lee JH, Hwang DW, Kim SC, Jang SJ, Hong SM, Kim TW, Ryoo BY. Therapeutic relevance of targeted sequencing in management of patients with advanced biliary tract cancer: DNA damage repair gene mutations as a predictive biomarker. Eur J Cancer 2019; 120:31-39. [DOI: 10.1016/j.ejca.2019.07.022] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 07/07/2019] [Accepted: 07/20/2019] [Indexed: 01/08/2023]
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Ettrich TJ, Schwerdel D, Dolnik A, Beuter F, Blätte TJ, Schmidt SA, Stanescu-Siegmund N, Steinacker J, Marienfeld R, Kleger A, Bullinger L, Seufferlein T, Berger AW. Genotyping of circulating tumor DNA in cholangiocarcinoma reveals diagnostic and prognostic information. Sci Rep 2019; 9:13261. [PMID: 31519967 PMCID: PMC6744511 DOI: 10.1038/s41598-019-49860-0] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 08/29/2019] [Indexed: 12/13/2022] Open
Abstract
Diagnosis of Cholangiocarcinoma (CCA) is difficult, thus a noninvasive approach towards (i) assessing and (ii) monitoring the tumor-specific mutational profile is desirable to improve diagnosis and tailor treatment. Tumor tissue and corresponding ctDNA samples were collected from patients with CCA prior to and during chemotherapy and were subjected to deep sequencing of 15 genes frequently mutated in CCA. A set of ctDNA samples was also submitted for 710 gene oncopanel sequencing to identify progression signatures. The blood/tissue concordance was 74% overall and 92% for intrahepatic tumors only. Variant allele frequency (VAF) in ctDNA correlated with tumor load and in the group of intrahepatic CCA with PFS. 63% of therapy naive patients had their mutational profile changed during chemotherapy. A set of 76 potential progression driver genes was identified among 710 candidates. The molecular landscape of CCA is accessible via ctDNA. This could be helpful to facilitate diagnosis and personalize and adapt therapeutic strategies.
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Affiliation(s)
- T J Ettrich
- University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine I, University of Ulm, Ulm, Germany
| | - D Schwerdel
- University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine I, University of Ulm, Ulm, Germany
| | - A Dolnik
- Charité University Medical Center Berlin, Department of Hematology, Oncology and Tumorimmunology, Berlin, Germany
| | - F Beuter
- University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine I, University of Ulm, Ulm, Germany
| | - T J Blätte
- University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine III, University of Ulm, Ulm, Germany
| | - S A Schmidt
- University Medical Center Ulm, Department of Diagnostic and Interventional Radiology, University of Ulm, Ulm, Germany
| | - N Stanescu-Siegmund
- University Medical Center Ulm, Department of Diagnostic and Interventional Radiology, University of Ulm, Ulm, Germany
| | - J Steinacker
- University Medical Center Ulm, Department of Diagnostic and Interventional Radiology, University of Ulm, Ulm, Germany
| | - R Marienfeld
- University Medical Center Ulm, Institute of Pathology, University of Ulm, Ulm, Germany
| | - A Kleger
- University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine I, University of Ulm, Ulm, Germany
| | - L Bullinger
- Charité University Medical Center Berlin, Department of Hematology, Oncology and Tumorimmunology, Berlin, Germany
| | - T Seufferlein
- University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine I, University of Ulm, Ulm, Germany.
| | - A W Berger
- University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine I, University of Ulm, Ulm, Germany.,Department of Gastroenterology, Gastrointestinal Oncology and Interventional Endoscopy, Vivantes Klinikum im Friedrichshain, Teaching Hospital of Charité - University Medical Center Berlin, Berlin, Germany
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40
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Brackett DG, Neyaz A, Arora K, Masia R, Mattia A, Zukerberg L, Misdraji J, Goyal L, Zhu AX, Ferrone CR, Yilmaz OH, Deshpande V. Cholangiolar pattern and albumin in situ hybridisation enable a diagnosis of intrahepatic cholangiocarcinoma. J Clin Pathol 2019; 73:23-29. [PMID: 31422372 DOI: 10.1136/jclinpath-2019-206055] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 07/29/2019] [Accepted: 07/30/2019] [Indexed: 12/15/2022]
Abstract
AIMS The histological distinction of intrahepatic cholangiocarcinoma (ICC) from metastatic adenocarcinoma remains a challenge. The primary goal was to evaluate the diagnostic value of morphology and albumin expression in the diagnosis of ICC. METHODS We evaluated morphological patterns in 120 ICCs and 677 non-hepatic adenocarcinomas and performed in situ hybridisation (ISH) stain for albumin in the former cohort (retrospective cohort). We also identified 119 samples from primary and metastatic lesions, the validation cohort, in which albumin ISH was performed as part of the diagnostic workup. Targeted sequencing was performed on selected cases. We also mined existing expression profiling data including cases from The Cancer Genome Atlas (TCGA) (41 760 unique samples). RESULTS In the retrospective cohort, 45% of ICCs and <1% of non-hepatic adenocarcinomas showed a cholangiolar pattern; albumin ISH was positive in 93% of ICCs with significant intratumorous heterogeneity. In the validation cohort, 29% of ICCs showed a cholangiolar pattern and 88% expressed albumin, while all metastatic non-hepatic neoplasms were negative (n=37) (sensitivity 88% and specificity 100%). Targetable genetic alterations (IDH mutations and FGFR2 fusions) were identified in 31% of ICCs (10 of 32). An analysis of the TCGA data validated the specificity of the albumin assay. CONCLUSIONS The cholangiolar pattern and albumin RNA ISH distinguishes ICC from metastatic adenocarcinoma with high specificity. Given the high prevalence of targetable mutations in ICC, albumin RNA ISH is an essential component in the workup of tumours of uncertain origin. A specific diagnosis of ICC could trigger molecular testing and uncover targetable genetic alterations.
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Affiliation(s)
- Diane G Brackett
- Depatment of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Azfar Neyaz
- Depatment of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Kshitij Arora
- Depatment of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Ricard Masia
- Depatment of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Anthony Mattia
- Depatment of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Lawerence Zukerberg
- Depatment of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Joseph Misdraji
- Depatment of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Lipika Goyal
- Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Andrew X Zhu
- Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Cristina R Ferrone
- Depatment of General and Gastrointestinal Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Omer H Yilmaz
- Depatment of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Vikram Deshpande
- Depatment of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
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41
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The Mitochondrion as an Emerging Therapeutic Target in Cancer. Trends Mol Med 2019; 26:119-134. [PMID: 31327706 DOI: 10.1016/j.molmed.2019.06.009] [Citation(s) in RCA: 136] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 06/10/2019] [Accepted: 06/14/2019] [Indexed: 12/11/2022]
Abstract
Mitochondria have emerged as important pharmacological targets because of their key role in cellular proliferation and death. In tumor tissues, mitochondria can switch metabolic phenotypes to meet the challenges of high energy demand and macromolecular synthesis. Furthermore, mitochondria can engage in crosstalk with the tumor microenvironment, and signals from cancer-associated fibroblasts can impinge on mitochondria. Cancer cells can also acquire a hybrid phenotype in which both glycolysis and oxidative phosphorylation (OXPHOS) can be utilized. This hybrid phenotype can facilitate metabolic plasticity of cancer cells more specifically in metastasis and therapy-resistance. In light of the metabolic heterogeneity and plasticity of cancer cells that had until recently remained unappreciated, strategies targeting cancer metabolic dependency appear to be promising in the development of novel and effective cancer therapeutics.
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42
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Jung C, Lavole J, Barret M, Abou Ali E, Palmieri LJ, Dermine S, Barré A, Chaussade S, Coriat R. Local Therapy in Advanced Cholangiocarcinoma: A Review of Current Endoscopic, Medical, and Oncologic Treatment Options. Oncology 2019; 97:191-201. [DOI: 10.1159/000500832] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 05/04/2019] [Indexed: 12/07/2022]
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Lamarca A, Barriuso J, Chander A, McNamara MG, Hubner RA, ÓReilly D, Manoharan P, Valle JW. 18F-fluorodeoxyglucose positron emission tomography ( 18FDG-PET) for patients with biliary tract cancer: Systematic review and meta-analysis. J Hepatol 2019; 71:115-129. [PMID: 30797051 DOI: 10.1016/j.jhep.2019.01.038] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 01/10/2019] [Accepted: 01/30/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS The role of 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) in the diagnosis and staging of patients with biliary tract cancers (BTCs) remains controversial, so we aimed to provide robust information on the utility of 18FDG-PET in the diagnosis and management of BTC. METHODS This systematic review and meta-analysis explored the diagnostic test accuracy of 18FDG-PET as a diagnostic tool for diagnosis of primary tumour, lymph node invasion, distant metastases and relapsed disease. Subgroup analysis by study quality and BTC subtype were performed. Changes in management based on 18FDG-PET and impact of maximum standardised uptake values (SUVmax) on prognosis were also assessed. A random effects model was used for meta-analyses. RESULTS A total of 2,125 patients were included from 47 eligible studies. The sensitivity (Se) and specificity (Sp) of 18FDG-PET for the diagnosis of primary tumour were 91.7% (95% CI 89.8-93.2) and 51.3% (95% CI 46.4-56.2), respectively, with an area under the curve (AUC) of 0.8668. For lymph node invasion, Se was 88.4% (95% CI82.6-92.8) and Sp was 69.1% (95% CI 63.8-74.1); AUC 0.8519. For distant metastases, Se was 85.4% (95% CI 79.5-90.2) and Sp was 89.7% (95% CI86.0-92.7); AUC 0.9253. For relapse, Se was 90.1% (95% CI 84.4-94.3) and Sp was 83.5% (95% CI 74.4-90.4); AUC 0.9592. No diagnostic threshold effect was identified. Meta-regression did not identify significant sources of heterogeneity. Sensitivity analysis revealed no change in results when analyses were limited to studies with low risk of bias/concern. The pooled proportion of change in management was 15% (95% CI 11-20); the majority (78%) due to disease upstaging. Baseline high SUVmax was associated with worse survival (pooled hazard ratio of 1.79; 95% CI 1.37-2.33; p <0.001). CONCLUSIONS There is evidence to support the incorporation of 18FDG-PET into the current standard of care for the staging (lymph node and distant metastases) and identification of relapse in patients with BTC to guide treatment selection; especially if the identification of occult sites of disease would change management, or if diagnosis of relapse remains unclear following standard of care imaging. The role for diagnosis of the primary tumour remains controversial due to low sensitivity and 18FDG-PET should not be considered as a replacement for pathological confirmation in this setting. LAY SUMMARY A positron emission tomography (PET scan), using 18F-fluorodeoxyglucose (18FDG), can help doctors identify areas of cancer in the body by highlighting "hot spots". These hotspots may be cancerous (true positive) but may also be non-cancerous, like inflammation (false positive). We show that PET scans are useful to assess how far advanced the cancer is (by assessing spread to lymph glands and to other organs) and also to identify if the cancer has recurred (for example after surgery), thus helping doctors to make treatment decisions. However, a biopsy is still needed for the initial diagnosis of a biliary tract cancer, because of the high chance of a "false positive" with PET scans.
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Affiliation(s)
- Angela Lamarca
- Medical Oncology Department, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, University of Manchester, UK.
| | - Jorge Barriuso
- Medical Oncology Department, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, University of Manchester, UK
| | - Amarjot Chander
- Radiology and Nuclear Medicine Department, The Christie NHS Foundation Trust, Manchester, UK
| | - Mairéad G McNamara
- Medical Oncology Department, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, University of Manchester, UK
| | - Richard A Hubner
- Medical Oncology Department, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, University of Manchester, UK
| | - Derek ÓReilly
- HPB Surgery Department, Manchester Royal Infirmary, Central Manchester University Hospitals, Manchester, UK
| | - Prakash Manoharan
- Radiology and Nuclear Medicine Department, The Christie NHS Foundation Trust, Manchester, UK
| | - Juan W Valle
- Medical Oncology Department, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, University of Manchester, UK.
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O'Rourke CJ, Lafuente-Barquero J, Andersen JB. Epigenome Remodeling in Cholangiocarcinoma. Trends Cancer 2019; 5:335-350. [PMID: 31208696 DOI: 10.1016/j.trecan.2019.05.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 05/03/2019] [Accepted: 05/07/2019] [Indexed: 12/22/2022]
Abstract
Cholangiocarcinoma (CCA) comprises a heterogeneous collection of malignancies arising within the biliary tract, characterized by late diagnosis, innate chemoresistance, and abysmal prognosis. Sequencing data have uncovered recurrent mutations in diverse epigenetic regulators, implicating epigenetic destabilization at the root of these tumors. However, few studies have characterized biliary tumor epigenomes. In this Opinion article, we argue that an epigenome-oriented approach to CCA could establish diverse interconnections between many key aspects of research on this disease, including molecular heterogeneity, diverse cells of origin, and prominent tumor microenvironments. Moreover, we discuss plausible causes of epigenome dysregulation in biliary tumors, including genetic, epigenetic, metabolic, microenvironmental, and physiological factors. Lastly, we assess the translational potential of epigenomics in CCA to uncover robust biomarkers and therapeutic opportunities for this growing group of patients with limited treatment options.
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Affiliation(s)
- Colm J O'Rourke
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Juan Lafuente-Barquero
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Jesper B Andersen
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
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Saeed A, Park R, Al-Jumayli M, Al-Rajabi R, Sun W. Biologics, Immunotherapy, and Future Directions in the Treatment of Advanced Cholangiocarcinoma. Clin Colorectal Cancer 2019; 18:81-90. [DOI: 10.1016/j.clcc.2019.02.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 02/15/2019] [Accepted: 02/18/2019] [Indexed: 02/07/2023]
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Golub D, Iyengar N, Dogra S, Wong T, Bready D, Tang K, Modrek AS, Placantonakis DG. Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics. Front Oncol 2019; 9:417. [PMID: 31165048 PMCID: PMC6534082 DOI: 10.3389/fonc.2019.00417] [Citation(s) in RCA: 180] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Accepted: 05/02/2019] [Indexed: 12/15/2022] Open
Abstract
The identification of heterozygous neomorphic isocitrate dehydrogenase (IDH) mutations across multiple cancer types including both solid and hematologic malignancies has revolutionized our understanding of oncogenesis in these malignancies and the potential for targeted therapeutics using small molecule inhibitors. The neomorphic mutation in IDH generates an oncometabolite product, 2-hydroxyglutarate (2HG), which has been linked to the disruption of metabolic and epigenetic mechanisms responsible for cellular differentiation and is likely an early and critical contributor to oncogenesis. In the past 2 years, two mutant IDH (mutIDH) inhibitors, Enasidenib (AG-221), and Ivosidenib (AG-120), have been FDA-approved for IDH-mutant relapsed or refractory acute myeloid leukemia (AML) based on phase 1 safety and efficacy data and continue to be studied in trials in hematologic malignancies, as well as in glioma, cholangiocarcinoma, and chondrosarcoma. In this review, we will summarize the molecular pathways and oncogenic consequences associated with mutIDH with a particular emphasis on glioma and AML, and systematically review the development and preclinical testing of mutIDH inhibitors. Existing clinical data in both hematologic and solid tumors will likewise be reviewed followed by a discussion on the potential limitations of mutIDH inhibitor monotherapy and potential routes for treatment optimization using combination therapy.
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Affiliation(s)
- Danielle Golub
- Department of Neurosurgery, New York University School of Medicine, NYU Langone Health, New York, NY, United States.,Clinical and Translational Science Institute, New York University School of Medicine, NYU Langone Health, New York, NY, United States
| | - Nishanth Iyengar
- New York University School of Medicine, NYU Langone Health, New York, NY, United States
| | - Siddhant Dogra
- New York University School of Medicine, NYU Langone Health, New York, NY, United States
| | - Taylor Wong
- Department of Neurosurgery, New York University School of Medicine, NYU Langone Health, New York, NY, United States
| | - Devin Bready
- Department of Neurosurgery, New York University School of Medicine, NYU Langone Health, New York, NY, United States
| | - Karen Tang
- Clinical and Translational Science Institute, New York University School of Medicine, NYU Langone Health, New York, NY, United States.,Division of Hematology/Oncology, Department of Pediatrics, New York University School of Medicine, NYU Langone Health, New York, NY, United States
| | - Aram S Modrek
- Department of Radiation Oncology, New York University School of Medicine, NYU Langone Health, New York, NY, United States
| | - Dimitris G Placantonakis
- Department of Neurosurgery, New York University School of Medicine, NYU Langone Health, New York, NY, United States.,Kimmel Center for Stem Cell Biology, New York University School of Medicine, NYU Langone Health, New York, NY, United States.,Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY, United States.,Brain Tumor Center, New York University School of Medicine, NYU Langone Health, New York, NY, United States.,Neuroscience Institute, New York University School of Medicine, NYU Langone Health, New York, NY, United States
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47
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Adeva J, Sangro B, Salati M, Edeline J, La Casta A, Bittoni A, Berardi R, Bruix J, Valle JW. Medical treatment for cholangiocarcinoma. Liver Int 2019; 39 Suppl 1:123-142. [PMID: 30892822 DOI: 10.1111/liv.14100] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Revised: 03/10/2019] [Accepted: 03/12/2019] [Indexed: 02/13/2023]
Abstract
Most of the patients with cholangiocarcinoma (CCA) present with advanced (inoperable or metastatic) disease, and relapse rates are high in those undergoing potentially curative resection. Previous treatment nihilism of patients with advanced disease has been replaced by active clinical research with the advent of randomized clinical trials (RCTs) and a much greater effort at understanding molecular mechanisms underpinning CCA. Three RCTs have recently been reported evaluating adjuvant chemotherapy following curative resection; only one of these has the potential to change practice. The BILCAP study failed to meet its primary endpoint by intention-to-treat analysis; however, a survival benefit was seen in a preplanned sensitivity analysis (predominantly adjusting for lymph nodes status). This, along with the numerical difference in median overall survival has led to the uptake of adjuvant capecitabine by many clinicians. In patients with advanced disease, the only level 1 data available supports the use of cisplatin and gemcitabine for the first-line treatment of patients with advanced disease; there is no established second-line chemotherapy. Previous forays into targeted therapy have proven unfruitful (namely targeting the epithelial growth factor receptor and vascular endothelial growth factor pathways). An increasing number of genomic subtypes are being defined; for some of these on-target therapeutic options are under active investigation. The most developed are studies targeting IDH-1 (isocitrate dehydrogenase) mutations and FGFR-2 (fibroblast growth factor receptor) fusions, with promising early results. Several other pathways are under evaluation, along with early studies targeting the immune environment; these are too premature to change practice to date. These emerging treatments are discussed.
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Affiliation(s)
- Jorge Adeva
- Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Bruno Sangro
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain
| | - Maximiliano Salati
- Department of Oncology, University Hospital of Modena and Reggio Emilia, Modena, Italy
- Division of Molecular Pathology, Institute of Cancer Research and Gastrointestinal Unit, Royal Marsden Hospital, London and Sutton, UK
| | - Julien Edeline
- Department of Medical Oncology, Centre Eugene Marquis, Rennes, France
| | - Adelaida La Casta
- Department of Medical Oncology, Hospital Universitario Donostia, Navarra, Spain
| | - Alessandro Bittoni
- Clinica Oncologica, Università Politecnica delle Marche, Ospedali Riuniti, Ancona, Italy
| | - Rosanna Berardi
- Clinica Oncologica, Università Politecnica delle Marche, Ospedali Riuniti, Ancona, Italy
| | - Jordi Bruix
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Juan W Valle
- Division of Cancer Sciences, University of Manchester, Manchester, UK
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
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48
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Primrose JN, Fox RP, Palmer DH, Malik HZ, Prasad R, Mirza D, Anthony A, Corrie P, Falk S, Finch-Jones M, Wasan H, Ross P, Wall L, Wadsley J, Evans JTR, Stocken D, Praseedom R, Ma YT, Davidson B, Neoptolemos JP, Iveson T, Raftery J, Zhu S, Cunningham D, Garden OJ, Stubbs C, Valle JW, Bridgewater J. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol 2019; 20:663-673. [PMID: 30922733 DOI: 10.1016/s1470-2045(18)30915-x] [Citation(s) in RCA: 800] [Impact Index Per Article: 133.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 11/28/2018] [Accepted: 11/29/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Despite improvements in multidisciplinary management, patients with biliary tract cancer have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. To our knowledge, no studies have described a benefit of adjuvant therapy. We aimed to determine whether adjuvant capecitabine improved overall survival compared with observation following surgery for biliary tract cancer. METHODS This randomised, controlled, multicentre, phase 3 study was done across 44 specialist hepatopancreatobiliary centres in the UK. Eligible patients were aged 18 years or older and had histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer who had undergone a macroscopically complete resection (which includes liver resection, pancreatic resection, or, less commonly, both) with curative intent, and an Eastern Cooperative Oncology Group performance status of less than 2. Patients who had not completely recovered from previous surgery or who had previous chemotherapy or radiotherapy for biliary tract cancer were also excluded. Patients were randomly assigned 1:1 to receive oral capecitabine (1250 mg/m2 twice daily on days 1-14 of a 21-day cycle, for eight cycles) or observation commencing within 16 weeks of surgery. Treatment was not masked, and allocation concealment was achieved with a computerised minimisation algorithm that stratified patients by surgical centre, site of disease, resection status, and performance status. The primary outcome was overall survival. As prespecified, analyses were done by intention to treat and per protocol. This study is registered with EudraCT, number 2005-003318-13. FINDINGS Between March 15, 2006, and Dec 4, 2014, 447 patients were enrolled; 223 patients with biliary tract cancer resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. The data cutoff for this analysis was March 6, 2017. The median follow-up for all patients was 60 months (IQR 37-60). In the intention-to-treat analysis, median overall survival was 51·1 months (95% CI 34·6-59·1) in the capecitabine group compared with 36·4 months (29·7-44·5) in the observation group (adjusted hazard ratio [HR] 0·81, 95% CI 0·63-1·04; p=0·097). In a protocol-specified sensitivity analysis, adjusting for minimisation factors and nodal status, grade, and gender, the overall survival HR was 0·71 (95% CI 0·55-0·92; p=0·010). In the prespecified per-protocol analysis (210 patients in the capecitabine group and 220 in the observation group), median overall survival was 53 months (95% CI 40 to not reached) in the capecitabine group and 36 months (30-44) in the observation group (adjusted HR 0·75, 95% CI 0·58-0·97; p=0·028). In the intention-to-treat analysis, median recurrence-free survival was 24·4 months (95% CI 18·6-35·9) in the capecitabine group and 17·5 months (12·0-23·8) in the observation group. In the per-protocol analysis, median recurrence-free survival was 25·9 months (95% CI 19·8-46·3) in the capecitabine group and 17·4 months (12·0-23·7) in the observation group. Adverse events were measured in the capecitabine group only, and of the 213 patients who received at least one cycle, 94 (44%) had at least one grade 3 toxicity, the most frequent of which were hand-foot syndrome in 43 (20%) patients, diarrhoea in 16 (8%) patients, and fatigue in 16 (8%) patients. One (<1%) patient had grade 4 cardiac ischaemia or infarction. Serious adverse events were observed in 47 (21%) of 223 patients in the capecitabine group and 22 (10%) of 224 patients in the observation group. No deaths were deemed to be treatment related. INTERPRETATION Although this study did not meet its primary endpoint of improving overall survival in the intention-to-treat population, the prespecified sensitivity and per-protocol analyses suggest that capecitabine can improve overall survival in patients with resected biliary tract cancer when used as adjuvant chemotherapy following surgery and could be considered as standard of care. Furthermore, the safety profile is manageable, supporting the use of capecitabine in this setting. FUNDING Cancer Research UK and Roche.
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Affiliation(s)
- John N Primrose
- Department of Surgery, University of Southampton, Southampton, UK.
| | - Richard P Fox
- Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK
| | - Daniel H Palmer
- University of Liverpool and Clatterbridge Cancer Centre, Liverpool, UK
| | | | - Raj Prasad
- Department of Surgery, University of Leeds, Leeds, UK
| | - Darius Mirza
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; Women's Children's Hospital NHS Foundation Trust, Birmingham, UK
| | | | - Pippa Corrie
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Stephen Falk
- University of Bristol Hospitals NHS Foundation Trust, Bristol, UK
| | - Meg Finch-Jones
- University of Bristol Hospitals NHS Foundation Trust, Bristol, UK
| | | | - Paul Ross
- Guys and St Thomas' NHS Foundation Trust, London, UK
| | - Lucy Wall
- Lothian University Hospitals NHS Trust, Edinburgh, UK
| | | | - Jeff T R Evans
- Department of Oncology, University of Glasgow, Glasgow, UK
| | - Deborah Stocken
- Faculty of Medicine and Health, University of Leeds, Leeds, UK
| | | | - Yuk Ting Ma
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Brian Davidson
- Department of General Surgery, University College London Hospital, London, UK
| | | | - Tim Iveson
- University Hospitals Southampton, Southampton, UK
| | - James Raftery
- Health Economics Analysis Team, University of Southampton, Southampton, UK
| | - Shihua Zhu
- Health Economics Analysis Team, University of Southampton, Southampton, UK
| | | | - O James Garden
- Department of Medicine, University of Edinburgh, Edinburgh, UK
| | - Clive Stubbs
- Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK
| | - Juan W Valle
- University of Manchester and The Christie NHS Foundation Trust, Manchester, UK
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Xie C, Duffy AG, Mabry-Hrones D, Wood B, Levy E, Krishnasamy V, Khan J, Wei JS, Agdashian D, Tyagi M, Gangalapudi V, Fioravanti S, Walker M, Anderson V, Venzon D, Figg WD, Sandhu M, Kleiner DE, Morelli MP, Floudas CS, Brar G, Steinberg SM, Korangy F, Greten TF. Tremelimumab in Combination With Microwave Ablation in Patients With Refractory Biliary Tract Cancer. Hepatology 2019; 69:2048-2060. [PMID: 30578687 PMCID: PMC6461476 DOI: 10.1002/hep.30482] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 12/11/2018] [Indexed: 12/15/2022]
Abstract
Treatment options for patients with advanced biliary tract cancer are limited. Dysregulation of the immune system plays an important role in the pathogenesis of biliary tract cancer (BTC). This study aimed to investigate whether tremelimumab, an anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, could be combined safely with microwave ablation to enhance the effect of anti-CTLA4 treatment in patients with advanced BTC. Patients were enrolled to receive monthly tremelimumab (10 mg/kg, intravenously) for six doses, followed by infusions every 3 months until off-treatment criteria were met. Thirty-six days after the first tremelimumab dose, patients underwent subtotal microwave ablation. Interval imaging studies were performed every 8 weeks. Adverse events (AEs) were noted and managed. Tumor and peripheral blood samples were collected to perform immune monitoring and whole-exome sequencing (WES). Twenty patients with refractory BTC were enrolled (median age, 56.5 years). No dose-limiting toxicities were encountered. The common treatment-related AEs included lymphopenia, diarrhea, and elevated transaminases. Among 16 patients evaluable for efficacy analysis, 2 (12.5%) patients achieved a confirmed partial response (lasting for 8.0 and 18.1 months, respectively) and 5 patients (31.3%) achieved stable disease. Median progression free survival (PFS) and overall survival (OS) were 3.4 months (95% confidence interval [CI], 2.5-5.2) and 6.0 months (95% CI, 3.8-8.8), respectively. Peripheral blood immune cell subset profiling showed increased circulating activated human leukocyte antigen, DR isotype ([HLA-DR] positive) CD8+ T cells. T-cell receptor (TCR)β screening showed tremelimumab expanded TCR repertoire, but not reaching statistical significance (P = 0.057). Conclusion: Tremelimumab in combination with tumor ablation is a potential treatment strategy for patients with advanced BTC. Increased circulating activated CD8+ T cells and TCR repertoire expansion induced by tremelimumab may contribute to treatment benefit.
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Affiliation(s)
- Changqing Xie
- Hematology/Oncology Fellowship Program, National Heart, Lung, and Blood Institute/National Cancer Institute, National Institutes of Health
| | - Austin G. Duffy
- Gastrointestinal Malignancies Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health
| | - Donna Mabry-Hrones
- Gastrointestinal Malignancies Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health
| | - Bradford Wood
- Radiology and Imaging Sciences, Center for Cancer Research, National Institutes of Health
| | - Elliot Levy
- Radiology and Imaging Sciences, Center for Cancer Research, National Institutes of Health
| | - Venkatesh Krishnasamy
- Radiology and Imaging Sciences, Center for Cancer Research, National Institutes of Health
| | - Javed Khan
- Genetics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Jun S. Wei
- Genetics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - David Agdashian
- Gastrointestinal Malignancies Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health
| | - Manoj Tyagi
- Genetics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | | | - Suzanne Fioravanti
- Gastrointestinal Malignancies Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health
| | - Melissa Walker
- Gastrointestinal Malignancies Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health
| | - Victoria Anderson
- Radiology and Imaging Sciences, Center for Cancer Research, National Institutes of Health
| | - David Venzon
- Biostatistics and Data Management Section, NCI, NIH, Bethesda, Maryland
| | - William D. Figg
- Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health
| | - Milan Sandhu
- Gastrointestinal Malignancies Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health
| | - David E. Kleiner
- Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health
| | - Maria Pia Morelli
- Hematology/Oncology Fellowship Program, National Heart, Lung, and Blood Institute/National Cancer Institute, National Institutes of Health
| | - Charalampos S Floudas
- Hematology/Oncology Fellowship Program, National Heart, Lung, and Blood Institute/National Cancer Institute, National Institutes of Health
| | - Gagandeep Brar
- Hematology/Oncology Fellowship Program, National Heart, Lung, and Blood Institute/National Cancer Institute, National Institutes of Health
| | - Seth M. Steinberg
- Biostatistics and Data Management Section, Center for Cancer Research, National Institutes of Health
| | - Firouzeh Korangy
- Gastrointestinal Malignancies Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health
| | - Tim F. Greten
- Gastrointestinal Malignancies Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health,NCI CCR Liver Cancer Program
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50
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Fan B, Mellinghoff IK, Wen PY, Lowery MA, Goyal L, Tap WD, Pandya SS, Manyak E, Jiang L, Liu G, Nimkar T, Gliser C, Prahl Judge M, Agresta S, Yang H, Dai D. Clinical pharmacokinetics and pharmacodynamics of ivosidenib, an oral, targeted inhibitor of mutant IDH1, in patients with advanced solid tumors. Invest New Drugs 2019; 38:433-444. [PMID: 31028664 PMCID: PMC7066280 DOI: 10.1007/s10637-019-00771-x] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 03/28/2019] [Indexed: 01/25/2023]
Abstract
Background Mutant isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) enzymes produce the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib (AG-120) is a targeted mutant IDH1 inhibitor under evaluation in a phase 1 dose escalation and expansion study of IDH1-mutant advanced solid tumors including cholangiocarcinoma, chondrosarcoma, and glioma. We explored the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ivosidenib in these populations. Methods Ivosidenib was administered orally once (QD) or twice (BID) daily in continuous 28-day cycles; 168 patients received ≥1 dose within the range 100 mg BID to 1200 mg QD. PK and PD were assessed using validated liquid chromatography-tandem mass spectrometry assays. Results Ivosidenib demonstrated good oral exposure after single and multiple doses, was rapidly absorbed, and had a long terminal half-life (mean 40–102 h after single dose). Exposure increased less than dose proportionally. Steady state was reached by day 15, with moderate accumulation across all tumors (1.5- to 1.7-fold for area-under-the-curve at 500 mg QD). None of the intrinsic and extrinsic factors assessed affected ivosidenib exposure, including patient/disease characteristics and concomitant administration of weak CYP3A4 inhibitors/inducers. After multiple doses in patients with cholangiocarcinoma or chondrosarcoma, plasma 2-HG was reduced by up to 98%, to levels seen in healthy subjects. Exposure-response relationships for safety and efficacy outcomes were flat across the doses tested. Conclusions Ivosidenib demonstrated good oral exposure and a long half-life. Robust, persistent plasma 2-HG inhibition was observed in IDH1-mutant cholangiocarcinoma and chondrosarcoma. Ivosidenib 500 mg QD is an appropriate dose irrespective of various intrinsic and extrinsic factors. Trial RegistrationClinicalTrials.gov (NCT02073994).
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Affiliation(s)
- Bin Fan
- DMPK, Agios Pharmaceuticals, Inc., 88 Sidney Street, Cambridge, MA, 02139, USA.
| | - Ingo K Mellinghoff
- Departments of Neurology and Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Patrick Y Wen
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Maeve A Lowery
- Trinity St James Cancer Institute, Trinity College, Dublin, Ireland
| | - Lipika Goyal
- Department of Internal Medicine, Division of Hematology/Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - William D Tap
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Shuchi S Pandya
- Clinical Development, Agios Pharmaceuticals, Inc., Cambridge, MA, USA
| | - Erika Manyak
- DMPK, Agios Pharmaceuticals, Inc., 88 Sidney Street, Cambridge, MA, 02139, USA
| | - Liewen Jiang
- Biostatistics - Clinical Development, Agios Pharmaceuticals, Inc., Cambridge, MA, USA
| | - Guowen Liu
- DMPK, Agios Pharmaceuticals, Inc., 88 Sidney Street, Cambridge, MA, 02139, USA
| | - Tara Nimkar
- Clinical Operations - Clinical Development, Agios Pharmaceuticals, Inc., Cambridge, MA, USA
| | - Camelia Gliser
- Clinical Development, Agios Pharmaceuticals, Inc., Cambridge, MA, USA
| | - Molly Prahl Judge
- Clinical Development, Agios Pharmaceuticals, Inc., Cambridge, MA, USA
| | - Sam Agresta
- Clinical Development, Agios Pharmaceuticals, Inc., Cambridge, MA, USA
| | - Hua Yang
- DMPK, Agios Pharmaceuticals, Inc., 88 Sidney Street, Cambridge, MA, 02139, USA
| | - David Dai
- DMPK, Agios Pharmaceuticals, Inc., 88 Sidney Street, Cambridge, MA, 02139, USA
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